Antiparasitic Compounds

ABSTRACT

The present invention relates to isothiazoline compounds of formula (I). The compounds are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to veterinary compositions comprising said compounds.

FIELD OF THE INVENTION

The present invention includes spirocyclic derivatives havingparasiticidal activity. The present invention preferably includesspirocyclic azetidenyl-isobenzofuran derivatives having an isothiazolinemoiety. The present invention also includes processes of making saidspirocyclic derivatives, compositions comprising said spirocyclicderivatives, and methods of use thereof.

BACKGROUND

There is a need for improved antiparasitics, and in particular there isa need for improved insecticides and acaricides, particularly for use inanimal health. Furthermore, there is a need for improved topical andoral products with convenient administration. Still further, there is aneed for improved compositions which contains one or more activeantiparasitics, which can be used to effectively treat againstparasites. Such improvements would be particularly useful for thetreatment of animals including: birds (e.g., chickens and turkeys),fish, companion animals (e.g., cats, dogs, llamas, and horses), andlivestock (e.g., cattle, bison, swine, sheep, deer, elk, and goats).

Currently available insecticidal and acaricidal treatments for animalsdo not always demonstrate good activity, good speed of action, or a longduration of action. Most treatments contain hazardous chemicals that canhave serious consequences, including neurotoxicity and lethality fromaccidental ingestion. Persons applying these agents are generallyadvised to limit their exposure. Pet collars and tags have been utilizedto overcome some problems, but these are susceptible to chewing,ingestion, and subsequent toxicological effects to the animal. Thus,current treatments achieve varying degrees of success, which dependpartly on toxicity, method of administration, and efficacy.Additionally, some currently available agents are becoming ineffectivedue to parasitic resistance.

Despite the availability of effective, broad spectrum antiparasitics,there remains a need for safer and more convenient, efficacious, andenvironmentally friendly products that will overcome the ever-presentthreat of resistance development. The present invention includes newisothiazoline spiroazetidinyl-isobenzofuran derivatives whichdemonstrate such properties.

SUMMARY

The present invention includes compounds according to Formula (I),including stereoisomers, and pesticidal, veterinary, or pharmaceuticallyacceptable salts thereof:

whereineach R^(1A), R^(1B), and R^(1C) individually is hydrogen, alkyl,halogen, or haloalkyl;R² is haloalkyl;X is bond, C(O), SO₂, or C(O)NH;R³ is hydrogen, optionally substituted alkyl, optionally substitutedhaloalkyl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl,or a pesticidal, veterinary, or pharmaceutically acceptable saltthereof.In one embodiment, the invention includes compounds of Formula (I)wherein:

-   -   each R^(1A), R^(1B), and R^(1C) individually is halogen,        haloalkyl, or alkyl;    -   R² is haloalkyl;    -   X is a bond, C(O), SO₂, or C(O)NH; and    -   R³ is alkyl, haloalkyl, or aryl.        In one embodiment, the invention includes compounds of        Formula (I) wherein:    -   each R^(1A), R^(1B), and R^(1C) individually is halogen;    -   R² is perfluoroalkyl;    -   X is —C(O)—, —SO₂—, or —C(O)NH—; and    -   R³ is haloalkyl.        In one embodiment, the invention includes compounds of        Formula (I) wherein:    -   each R^(1A) and R^(1C) is a halogen and R^(1B) is a different        halogen;    -   R² is haloalkyl, preferably —CF₃;    -   X is —C(O)—; and    -   R³ is haloalkyl, preferably —CH₂CF₃.        In one embodiment, the invention includes compounds of        Formula (I) wherein:    -   each R^(1A) and R^(1C) is —Cl and R^(1B) is —F;    -   R² is —CF₃;    -   X is —C(O)—; and    -   R³ is haloalkyl, preferably —CH₂CF₃.        In one embodiment, the invention includes compounds of        Formula (I) wherein:    -   each R^(1A) and R^(1C) is —Cl and R^(1B) is —F;    -   R² is —CF₃;    -   X is a bond, C(O), SO₂, or C(O)NH; and    -   R³ is hydrogen, optionally substituted alkyl, optionally        substituted haloalkyl, optionally substituted cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        aryl, and optionally substituted heteroaryl.

In one or more embodiments, R³ is alkyl; alkyl substituted with one ormore alkoxy, alkylsulfonyl, cyano, or aryl; haloalkyl; cycloalkyl;cycloalkyl substituted with one or more alkyl, alkenyl, haloalkyl,haloalkenyl, alkoxy, or carbonyl; heterocyclyl; aryl; aryl substitutedwith one or more halogen; or heteroaryl.

One embodiment of the invention includes compositions comprising acompound of formula (I) along with a pesticidally acceptable carrier.The compositions of the invention can also be in a variety of formswhich include, but are not limited to, oral formulations, injectableformulations, and topical, dermal, or subdermal formulations. Theformulations are intended to be administered to an animal, whichincludes, but is not limited to, mammals, birds, and fish. Examples ofmammals include, but are not limited to, humans, cattle, sheep, goats,llamas, alpacas, pigs, horses, donkeys, dogs, cats, and other livestockor domestic mammals. Examples of birds include turkeys, chickens,ostriches, and other livestock or domestic birds.

The present invention includes compositions comprising a compound offormula (I) suitable for treatment of a locus that may be infected withparasites, such as a plant or animal such as a mammal, or for theprevention of infection or infestation of a locus with parasites.

Another embodiment of the present invention includes combinationtherapy, whereby one or more compounds of formula (I) can be employed assuch or in the form of their preparations or formulations ascombinations with one or more other pesticidally active substances, suchas, for example, insecticides, attractants, sterilants, nematicides,acaricides, fungicides, herbicides, and with safeners, fertilizers, orgrowth regulators. The combinations may be part of the same formulation,or may be administered separately or sequentially to the locus.

Another embodiment of the present invention includes a compound offormula (I), or a composition comprising a compound of formula (I), foruse in treating or preventing parasitic infection or infestation.

Another embodiment of the present invention includes the use of acompound of formula (I) for the manufacture of a medicament for use intreating or preventing parasitic infection or infestation.

Another embodiment of the present invention includes a method oftreating or preventing a parasitic infection comprising theadministration of an effective amount of a compound of formula (I), or acomposition comprising a compound of formula (I) to a locus.

One embodiment of the present invention is a compound of the presentinvention selected from:

-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one;-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-(2,2,2-trifluoroethyl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(4-fluorophenyl)sulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine];-   [6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-phenyl-methanone;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methylsulfonyl-ethanone;-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine];-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3-dimethyl-butan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]butan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-phenyl-ethanone;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4,4,4-trifluoro-butan-1-one;-   [6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-(1-naphthyl)methanone;-   [(3Z,4Z)-4-allylidene-3-ethylidene-cyclohexa-1,5-dien-1-yl]-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methanone;-   [6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-(4-morpholinophenyl)methanone;-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-propylsulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine];-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3,3-trifluoropropylsulfonyl)spiro[1H-isobenzofuran-3,3′-azetidine];-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-ethyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-phenyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;-   [6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropyl]methanone;-   [6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-tetrahydropyran-4-yl-methanone;-   1′-butyl-6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine];-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3-dimethylbutyl)spiro[1H-isobenzofuran-3,3′-azetidine];-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methoxy-ethanone;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-isopropoxy-ethanone;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-ethoxy-ethanone;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methyl-propan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]propan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]ethanone;-   3-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4-ethoxy-cyclobut-3-ene-1,2-dione;-   3-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3-oxo-propanenitrile;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2,3,3,3-pentafluoro-propan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2-difluoro-propan-1-one;-   [6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclopropyl]methanone;-   [6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclobutyl]methanone;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-2,2-dimethyl-propan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]pentan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]hexan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]heptan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]octan-1-one;-   1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]nonan-1-one;-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-pyrimidin-2-yl-spiro[1H-isobenzofuran-3,3′-azetidine];    and-   6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-methyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide,    or a pesticidal, veterinary, or pharmaceutically acceptable salt    thereof.

One embodiment of the present invention is a composition comprising acompound of the present invention and a pesticidally acceptable carrier.Another embodiment of the present invention is a combination comprisinga compound of the present invention and one or more other pesticidallyactive substances. Another embodiment of the present invention is amethod for controlling parasites at a locus comprising applying to thelocus an effective amount of a compound of the present invention.Another embodiment of the present invention is a method of treating orpreventing parasitic infection or infestation in a subject comprisingadministering to the subject an effective amount of a compound of thepresent invention. In one aspect, the parasite is a flea or tick. In oneaspect, the parasite is Ctenocephalides felis, R. sanguineus, D.variablis, A. americanum, or I. scapularis. In one aspect, the parasiteis a helminth. In one aspect, the parasite is Dirofilaria immitis.Another embodiment of the present invention is a compound of the presentinvention for use in treating or preventing parasitic infection orinfestation. Another embodiment is a compound of the present inventionfor use in medicine.

One embodiment of the present invention is a compound1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-oneor a pesticidal, veterinary, or pharmaceutically acceptable saltthereof. Another embodiment is a composition comprising1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-oneor a pesticidal, veterinary, or pharmaceutically acceptable salt thereofand one or more pesticidal, veterinary, or pharmaceutically acceptablecarrier. Another embodiment of the present invention is a combinationcomprising1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-oneor a pesticidal, veterinary, or pharmaceutically acceptable salt thereofand one or more other pesticidally active substances. Another embodimentof the present invention is a method for controlling parasites at alocus comprising applying to the locus an effective amount of1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-oneor a pesticidal, veterinary, or pharmaceutically acceptable saltthereof. Another embodiment of the present invention is a method oftreating or preventing parasitic infection or infestation in a subjectcomprising administering to the subject an effective amount of1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-oneor a pesticidal, veterinary, or pharmaceutically acceptable saltthereof. In one aspect, the parasite is a flea or tick. In one aspect,the parasite is Ctenocephalides felis, R. sanguineus, D. variablis, A.americanum, or I. scapularis. In one aspect, the parasite is a helminth.In one aspect, the parasite is Dirofilaria immitis. Another embodimentof the present invention is1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-oneor a pesticidal, veterinary, or pharmaceutically acceptable salt thereoffor use in treating or preventing parasitic infection or infestation.Another embodiment is1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-oneor a pesticidal, veterinary, or pharmaceutically acceptable salt thereoffor use in medicine.

DETAILED DESCRIPTION

One or more aspects and embodiments may be incorporated in a differentembodiment although not specifically described. That is, all aspects andembodiments can be combined in any way or combination.

Definitions

When referring to the compounds disclosed herein, the following termshave the following meanings unless indicated otherwise. The followingdefinitions are meant to clarify, but not limit, the terms defined. If aparticular term used herein is not specifically defined, such termshould not be considered indefinite. Rather, terms are used within theiraccepted meanings.

As used herein, the term “alkoxy” refers to the group —OR where R isalkyl. Illustrative alkoxy groups include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and1,2-dimethylbutoxy.

As used herein, “alkyl” refers to monovalent saturated aliphatichydrocarbyl groups having from 1 to 20 carbon atoms, preferably 1-8carbon atoms, preferably 1-6 carbon atoms. The hydrocarbon chain can beeither straight-chained or branched. Illustrative alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, and tert-butyl.Similarly, an “alkenyl” group refers to an alkyl group having one ormore double bonds present in the chain.

As used herein, “cycloalkyl” refers to an unsaturated or partiallysaturated hydrocarbon ring, containing from 3 to 6 ring atoms.Illustrative cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, as well as partially saturated versionsthereof, such as cyclohexenyl, and cyclohexadienyl.

As used herein “halogen” or “halo” refers to a halogen. In someembodiments, the halogen is preferably Br, Cl, or F.

As used herein, “haloalkyl” refers to monovalent saturated aliphatichydrocarbyl groups having from 1 to 20 carbon atoms, preferably 1-8carbon atoms, preferably 1-6 carbon atoms, wherein at least one hydrogenatom is substituted by a halogen, including but not limited to perhalogroups where all hydrogen atoms are replaced with halogen atoms. Thehaloalkyl chain can be either straight-chained or branched. Illustrativealkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl,trifluorobutyl, and pentafluoroethyl. Similarly, a “haloalkenyl” grouprefers to a haloalkyl group having one or more double bonds present inthe chain.

As used herein “heterocyclyl” or “heterocycle” refers to an unsaturatedor partially saturated ring containing from 3 to 6 ring atoms and from 1to 4 heteroatoms, which may be the same or different, selected fromnitrogen, oxygen and sulfur. Illustrative heterocyclyl groups includeoxirane, tetrahydrofuranyl, morpholino, pyrrolidinyl,tetrahydrothiophene, dioxane, and piperidinyl.

As used herein “aryl” refers to an aromatic ring system containing from5 to 10 ring atoms. Illustrative aryl groups include phenyl andnaphthyl.

As used herein “heteroaryl” refers to an heteroaromatic ring systemcontaining from 5 to 10 ring atoms and from 1 to 4 heteroatoms, whichmay be the same or different, selected from nitrogen, oxygen and sulfur.Illustrative heteroaryl groups include pyridyl (pyridinyl), furan,thiophene, pyrazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolyl, andpyrimidinyl.

As used herein “optionally substituted” refers to a substitution of ahydrogen atom, which would otherwise be present on the substituent. Whendiscussing ring systems, the optional substitution is typically with 1,2, or 3 substituents replacing the normally-present hydrogen. Whenreferencing straight and branched moieties, however, the number ofsubstitutions can be more, occurring wherever hydrogen is usuallypresent. The substitutions can be the same or different. Illustrativesubstitutions include nitro, —NR′R″, cyano, —NR′COR′″, alkyl, alkenyl,—C(O), —SO₂R′″, —NR′SO₂R′″, —SO₂NR′R″, —CONR′R″, —CONHC₆H₅, hydroxy,alkoxy, alkylsulfonyl, haloalkyl, haloalkenyl, haloalkoxy, mercapto(—SH), thioalkyl, halogen, cycloalkyl, heterocyclyl, aryl, orheteroaryl, where R′ and R″ are the same or different and eachrepresents hydrogen or alkyl; or when R′ and R″ are each attached to anitrogen atom, they may form a saturated or unsaturated heterocyclicring containing from 4 to 6 ring atoms, and wherein R′″ is alkyl orhaloalkyl.

As used herein the phrase pesticidal or pesticidally, veterinary orveterinarily, or pharmaceutical or pharmaceutically acceptable saltrefers to any salt of a compound disclosed herein which retains itsbiological properties and which is not toxic or otherwise undesirablefor pesticidal, veterinary, or pharmaceutical use. Such salts may bederived from a variety of organic and inorganic counter-ions known inthe art. Such salts include: (1) acid addition salts formed with organicor inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric,phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic,propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic,lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric,tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric,cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic,1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic,4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic,camphoric, camphorsulfonic,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic,3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric,gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic,cyclohexylsulfamic, quinic, muconic acid, and like acids.

Salts further include, by way of example only, salts of non-toxicorganic or inorganic acids, such as halides, such as, chloride andbromide, sulfate, phosphate, sulfamate, nitrate, acetate,trifluoroacetate, trichloroacetate, propionate, hexanoate,cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate,malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate,tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate,cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate),ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate,benzenesulfonate (besylate), 4-chlorobenzenesulfonate,2-naphthalenesulfonate, 4-toluenesulfonate, camphorate,camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate,glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate,lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate,salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and thelike.

In certain cases, the depicted substituents can contribute to opticaland/or stereoisomerism. Compounds having the same molecular formula butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space are termed “isomers.” Isomers thatdiffer in the arrangement of their atoms in space are termed“stereoisomers.” Stereoisomers that are not mirror images of one anotherare termed “diastereomers” and those that are non-superimposable mirrorimages of each other are termed “enantiomers”. When a compound has anasymmetric center, for example when it is bonded to four differentgroups, a pair of enantiomers is possible. An enantiomer can becharacterized by the absolute configuration of its asymmetric center andis designated (R) or (S) according to the rules of Cahn and Prelog (Cahnet al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5:385-414 (errata: Angew. Chem., Int. Ed. Engl. 5:511); Prelog andHelmchen, 1982, Angew. Chem. 94: 614-631, Angew. Chem. Internat. Ed.Eng. 21: 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4:657-668) or can be characterized by the manner in which the moleculerotates the plane of polarized light and is designated dextrorotatory orlevorotatory (namely, as (+)- or (−)-isomers, respectively). A chiralcompound can exist as either an individual enantiomer or as a mixturethereof. A mixture containing equal proportions of enantiomers is calleda “racemic mixture”.

In certain embodiments, the compounds disclosed herein can possess oneor more asymmetric centers; and such compounds can therefore be producedas the individual (R)- or (S)-enantiomer or as a mixture thereof. Unlessindicated otherwise, for example by designation of stereochemistry atany position of a formula, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof.Methods for determination of stereochemistry and separation ofstereoisomers are well-known in the art. In particular embodiments,stereoisomers of the compounds provided herein are depicted upontreatment with base.

In certain embodiments, the compounds disclosed herein are“stereochemically pure”. A stereochemically pure compound has a level ofstereochemical purity that would be recognized as “pure” by those ofskill in the art. Of course, this level of purity may be less than 100%.In certain embodiments, “stereochemically pure” designates a compoundthat is substantially free, i.e. at least about 85% or more, ofalternate isomers. In particular embodiments, the compound is at leastabout 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about99.9% free of other isomers.

As used herein, the terms “subject” and “patient” are usedinterchangeably herein. The terms “subject” and “subjects” refer to aprimate such as a monkey such as a cynomolgous monkey, a chimpanzee, anda human or non-primate animal. In one embodiment, the subject is ahuman. In another embodiment, the subject is a companion animal such asa dog or cat. In a further embodiment the subject is an animal ofagricultural importance such as a sheep, cow, horse, goat, fish, pig, ordomestic fowl (such as a chicken, turkey, duck, or goose).

In addition, a pharmaceutically acceptable prodrug of the compoundrepresented by the formula (I) is also included in the presentinvention. The pharmaceutically acceptable prodrug refers to a compoundhaving a group which can be converted into an amino group, a hydroxylgroup, a carboxyl group, or the like, by solvolysis or under aphysiological condition. Examples of the groups forming the prodruginclude those as described in Prog. Med., 5, 2157-2161 (1985) or“Pharmaceutical Research and Development” (Hirokawa Publishing Company,1990), vol. 7, Drug Design, 163-198. The term prodrug is used throughoutthe specification to describe any pharmaceutically acceptable form of acompound which, upon administration to a patient, provides the activecompound, Pharmaceutically acceptable prodrugs refer to a compound thatis metabolized, for example hydrolyzed or oxidized, in the host to formthe compound of the present invention. Typical examples of prodrugsinclude compounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat can be oxidized, reduced, aminated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, dephosphorylated to produce theactive compound.

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of the invention wherein one or moreatoms are replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen, such as ²Hand ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulfur, such as ³⁵S. Certain isotopically-labelled compounds of theinvention, such as those incorporating a radioactive isotope, may beuseful in drug or substrate tissue distribution studies. The radioactiveisotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴O, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection. Substitution with heavier isotopes such asdeuterium, i.e. ²H, may afford certain therapeutic advantages resultingfrom greater metabolic stability, for example, increased in vivohalf-life or reduced dosage requirements, and hence may be preferred insome circumstances. Substitution with positron emitting isotopes, suchas ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography(PET) studies for examining substrate receptor occupancy.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations using an appropriate isotopically-labeled reagents inplace of the non-labeled reagent previously employed.

Compounds

Isoxazoline derivatives have been disclosed in the art as havinginsecticidal and acaricidal activity. For example, WO2007/105814,WO2008/122375, and WO2009/035004 contain certain alkylene linked amides.WO2010/032437 discloses that the benzyl amide can be moved to theposition ortho to the isoxazoline. Further, WO2007/075459 disclosesphenyl isoxazolines substituted with 5- to 6-membered heterocycles, andWO2010/084067 and WO2010/025998 disclose phenyl isoxazolines substitutedwith 10- to 11-membered fused aryl and heteroaryls. Chiral processes formanufacturing isoxazolines have been reported in WO2011/104089 andWO2009/063910. Isoxazoline azetidine derivatives were published inWO2012/017359. Some spiro-azetidine isobenzofuran derivatives for thetreatment of diabetes and hyperlipidemia were described inWO2008/096746. In addition, spirocyclic isoxazolines were recentlypublished in WO2012/120399. WO2014/039489 discloses spirocyclicderivatives as antiparisitic agents, includingazetidinyl-isobenzofurans, but the citation does not teach or suggestisothiazolines as the heterocyclic moiety. WO2014/079935 discloses apreparation of [4-(isothiazol-3-yl)arylthio]acetamide derivatives asinsecticides, and WO2014/001121 and WO2014/001120 each disclose thepreparation of isothiazole derivatives as insecticidal compounds, butnone contain the azetidinyl-isobenzofuran. WO2014/206911 disclosesisothiazoline compounds, however, the teaching lacks anyazetidenyl-isobenzofuran moiety. WO2014/079941 discloses insecticidalcompounds based on N-(arylsulfanylmethyl) carboxamide derivatives.US2014378415 discloses isothiazoline compounds, however, the teachinglacks any azetidenyl-isobenzofuran moiety. WO2009/112275 relates topesticidal condensed-ring aryl compounds, however, the teaching lacksany azetidenyl-isobenzofuran moiety.

None of the foregoing references teach or suggest non-isoxazolinespirocyclic molecules, or processes of manufacturing such compounds. Nordo the foregoing citations indicate that such compounds would be usefulagainst a spectrum of parasitic species relevant to companion animals,livestock, birds, or fish, and especially against the range of parasiticmorphological lifecycle stages.

Synthesis

Generally the compounds of the invention can be prepared, isolated orobtained by any method apparent to those of skill in the art. Exemplarymethods of preparation are illustrated by the following schemes.

Alternatively, the isothiazoline can be formed according the belowscheme:

Compositions and Methods of Administration

The compounds of formula (I) used in the methods disclosed herein can beadministered in certain embodiments using veterinary, pharmaceutical, orpesticidal compositions including at least one compound of formula (I),if appropriate in the salt form, either used alone or in the form of acombination with one or more compatible and veterinarily,pharmaceutically, or pesticidally acceptable carriers, such as diluentsor adjuvants, or with another agent. There are provided compositionswhich comprise an isothiazoline derivative of formula (I) or a saltthereof, and an acceptable excipient, carrier or diluent. Thecomposition can also be in a variety of forms which include, but are notlimited to, oral formulations, injectable formulations, and topical,dermal or subdermal formulations.

The composition can be in a form suitable for oral use, for example, asdietary supplements, troches, lozenges, chewables, tablets, hard or softcapsules, emulsions, aqueous or oily suspensions, aqueous or oilysolutions, dispersible powders or granules, syrups, or elixirs.Compositions intended for oral use can be prepared according to anymethod known in the art for the manufacture of veterinary,pharmaceutical, or pesticidal compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, bittering agents, flavoring agents, coloring agentsand preserving agents in order to provide elegant and palatablepreparations.

Tablets can contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients can be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period.

Formulations for oral use can be hard gelatin capsules, wherein theactive ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin. Capsules can also besoft gelatin capsules, wherein the active ingredient is mixed with wateror miscible solvents such as propylene glycol, PEGs and ethanol, or anoil medium, for example, peanut oil, liquid paraffin, or olive oil.

The compositions can also be in the form of oil-in-water or water-in-oilemulsions. The oily phase can be a vegetable oil, for example, olive oilor arachis oil, or a mineral oil, for example, liquid paraffin ormixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example, soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan monoleate, and condensation productsof the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions can also containsweetening agents, bittering agents, flavoring agents, andpreservatives.

In one embodiment of the formulation, the composition is in the form ofa microemulsion. Microemulsions are well suited as the liquid carriervehicle. Microemulsions are quaternary systems comprising an aqueousphase, an oily phase, a surfactant and a cosurfactant. They aretranslucent and isotropic liquids. Microemulsions are composed of stabledispersions of microdroplets of the aqueous phase in the oily phase orconversely of microdroplets of the oily phase in the aqueous phase. Thesize of these microdroplets is less than 200 nm (1000 to 100,000 nm foremulsions). The interfacial film is composed of an alternation ofsurface-active (SA) and co-surface-active (Co-SA) molecules which, bylowering the interfacial tension, allows the microemulsion to be formedspontaneously. In one embodiment of the oily phase, the oily phase canbe formed from mineral or vegetable oils, from unsaturatedpolyglycosylated glycerides or from triglycerides, or alternatively frommixtures of such compounds. In one embodiment of the oily phase, theoily phase comprises of triglycerides; in another embodiment of the oilyphase, the triglycerides are medium-chain triglycerides, for example,C₈-C₁₀ caprylic/capric triglyceride. In another embodiment, the oilyphase will represent a % v/v range selected from the group consisting ofabout 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/vof the microemulsion. The aqueous phase includes, for example, water orglycol derivatives, such as propylene glycol, glycol ethers,polyethylene glycols or glycerol. In one embodiment of the glycolderivatives, the glycol is selected from the group consisting ofpropylene glycol, diethylene glycol monoethyl ether, dipropylene glycolmonoethyl ether and mixtures thereof. Generally, the aqueous phase willrepresent a proportion from about 1 to about 4% v/v in themicroemulsion. Surfactants for the microemulsion include diethyleneglycol monoethyl ether, dipropylene glycol monomethyl ether,polyglycolyzed C₈-C₁₀ glycerides or polyglyceryl-6 dioleate. In additionto these surfactants, the cosurfactants include short-chain alcohols,such as ethanol and propanol. Some compounds are common to the threecomponents discussed above, for example, aqueous phase, surfactant andcosurfactant. However, it is well within the skill level of thepractitioner to use different compounds for each component of the sameformulation. In one embodiment for the amount ofsurfactant/cosurfactant, the cosurfactant to surfactant ratio will befrom about 1/7 to about ½.

In another embodiment for the amount of cosurfactant, there will be fromabout 25 to about 75% v/v of surfactant and from about 10 to about 55%v/v of cosurfactant in the microemulsion.

Oily suspensions can be formulated by suspending the active ingredientin a vegetable oil, for example, atachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions can contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents can be added toprovide a palatable oral preparation. These compositions can bepreserved by the addition of an anti-oxidant such as ascorbic acid, orother known preservatives.

Aqueous suspensions can contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents can be a naturally-occuring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example, polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example, polyethylene sorbitan monooleate.The aqueous suspensions can also contain one or more preservatives, forexample, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, can also be present.

Syrups and elixirs can be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoringagent(s) and coloring agent(s).

The compositions can be in the form of a sterile injectable aqueous oroleagenous suspension. This suspension can be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation can also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. Cosolvents such as ethanol,propylene glycol or polyethylene glycols can also be used.Preservatives, such as phenol or benzyl alcohol, can be used.

In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil canbe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Topical, dermal and subdermal formulations can include emulsions,creams, ointments, gels or pastes.

Organic solvents that can be used in the invention include but are notlimited to: acetyltributyl citrate, fatty acid esters such as thedimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzylalcohol, butyl diglycol, dimethylacetamide, dimethylformamide,dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol,ethylene glycol monoethyl ether, ethylene glycol monomethyl ether,monomethylacetamide, dipropylene glycol monomethyl ether, liquidpolyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g.N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycoland diethyl phthalate, or a mixture of at least two of these solvents.

As vehicle or diluent, compositions of the present invention may includeplant oils such as, but not limited to soybean oil, groundnut oil,castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunfloweroil, etc.; mineral oils such as, but not limited to, petrolatum,paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons oralternatively, for example, medium-chain (such as C₈-C₁₂) triglycerides.

Dosage forms can contain from about 0.5 mg to about 5 g of an activeagent.

In one embodiment of the invention, the active agent is present in theformulation at a concentration of about 0.05 to 10% weight/volume.

The compounds of formula (I) can be employed as such or in the form oftheir preparations or formulations as combinations with otherpesticidally active substances, such as, for example, insecticides,attractants, sterilants, nematicides, acaricides, fungicides,herbicides, and with safeners, fertilizers and/or growth regulators.

The compounds of formula (I) according to the invention may be combinedwith one or more agents having the same sphere of activity, for example,to increase activity, or with substances having another sphere ofactivity, for example, to broaden the range of activity. The compoundsof the present invention may also be combined with so-called repellents.By combining the compounds of the formula I with other suitableparasiticides, not only the parasiticidal activity can be enhanced, butthe greatest part of those parasites that produce great economic damagewill be covered. Moreover, this action will contribute substantially toavoiding the formation of resistance. Preferred groups of combinationpartners and especially preferred combination partners are named in thefollowing, whereby combinations may contain one or more of thesepartners in addition to a compound of formula I. Suitable partners mayalso be afoxolaner, sarolaner, fluralaner, or a combination thereof. Anyof the individually listed agents can be used in combination withcompounds of formula (I) along with any other one or more listed agentsindependently.

Suitable partners in the mixture may be biocides, namely insecticidesand acaricides with a varying mechanism of activity, for example, chitinsynthesis inhibitors, growth regulators, active ingredients which act asjuvenile hormones, active ingredients which act as adulticides,broadband insecticides, broadband acaricides and nematicides, and alsoanthelminthics and insect- and acarid-deterring substances, repellentsor detachers. Non-limiting examples of suitable insecticides andacaricides are:

1. Abamectin 96. Dioxathion 191. Omethoate 2. Acephate 97. Disulfoton192. Oxamyl 3. Acequinocyl 98. DNOC 193. Oxydemethon M 4. Acetamiprid99. Doramectin 194. Oxydeprofos 5. Acetoprole 100. DPX-HGW86 195.Parathion 6. Acrinathrin 101. Edifenphos 196. Parathion-methyl 7.AKD-1022 102. Emamectin 197. Permethrin 8. Alanycarb 103. Empenthrin198. Phenothrin 9. Aldicarb 104. Endosulfan 199. Phenthoate 10.Aldoxycarb 105. Esfenvalerat 200. Phorate 11. Allethrin 106.Ethiofencarb 201. Phosalone 12. Alpha-cypermethrin 107. Ethion 202.Phosmet 13. Alphamethrin 108. Ethiprole 203. Phosphamidon 14.Amidoflumet 109. Ethoprophos 204. Phoxim 15. Amitraz 110. Etofenprox205. Pirimicarb 16. Anabasine 111. Etoxazole 206. Pirimiphos A 17.Avermectin B1 112. Etrimphos 207. Pirimiphos M 18. Azadirachtin 113.Fenamiphos 208. Polynactins 19. Azamethiphos 114. Fenazaquin 209.Prallethrin 20. Azinphos-ethyl 115. Fenbutatin oxide 210. Profenofos 21.Azinphos-methyl 116. Fenitrothion 211. Profluthrin 22. Azocyclotin 117.Fenobucarb 212. Promecarb 23. Bacillus subtil, toxin 118. Fenothiocarb213. Propafos 24. Bacillus thuringiensis 119. Fenoxycarb 214. Propargite25. Benclothiaz 120. Fenpropathrin 215. Propoxur 26. Bendiocarb 121.Fenpyroximate 216. Prothiofos 27. Benfuracarb 122. Fenthion 217.Prothoate 28. Bensultap 123. Fenvalerate 218. Protrifenbute 29.Benzoximate 124. Fipronil 219. Pymetrozine 30. Beta-cyfluthrin 125.Flonicamid 220. Pyrachlofos 31. Beta-cypermethrin 126. Fluacrypyrim 221.Pyrafluprole 32. Bifenazate 127. Fluazinam 222. Pyresmethrin 33.Bifenthrin 128. Fluazuron 223. Pyrethrin 34. Bioallethrin 129.Flubendiamide 224. Pyrethrum 35. Bioresmethrin 130. Flucycloxuron 225.Pyridaben 36. Bistrifluron 131. Flucythrinate 226. Pyridalyl 37. BPMC132. Flufenerim 227. Pyridaphenthion 38. Brofenprox 133. Flufenoxuron228. Pyrifluquinazon 39. Bromophos A 134. Flufenprox 229. Pyrimidifen40. Bromopropylate 135. Flumethrin 230. Pyriprole 41. Bufencarb 136.Fonophos 231. Pyriproxyfen 42. Buprofezin 137. Formothion 232.Quinalphos 43. Butocarboxim 138. Fosthiazate 233. Resmethrin 44.Cadusafos 139. Fubfenprox 234. Rotenone 45. Carbaryl 140. Furathiocarb235. RU 15525 46. Carbofuran 141. Gamma-cyhalothrin 236. Sabadilla 47.Carbophenothion 142. Halfenprox 237. Salithion 48. Carbosulfan 143.Halofenozide 238. Selamectin 49. Cartap 144. HCH 239. Silafluofen 50.Chloethocarb 145. Heptenophos 240. Spinetoram 51. Chlorantraniliprole146. Hexaflumuron 241. Spinosad 52. Chlorethoxyfos 147. Hexythiazox 242.Spirodiclofen 53. Chlorfenapyr 148. Hydramethylnon 243. Spiromesifen 54.Chlorfenvinphos 149. Hydroprene 244. Spirotetramat 55. Chlorfluazuron150. Imidacloprid 245. Sulcofuron sodium 56. Chlormephos 151.Imiprothrin 246. Sulfluramid 57. Chlorpyrifos 152. Indoxacarb 247.Sulfotep 58. Chlorpyrifos-methyl 153. insect-active fungi 248. Sulfur59. Chromafenozide 154. insect-active nematodes 249. Sulprofos 60.Cis-Resmethrin 155. insect-active viruses 250. Tau-fluvalinate 61.Clofentezin 156. Iprobenfos 251. Tebufenozide 62. Clothianidin 157.Lsofenphos 252. Tebufenpyrad 63. Coumaphos 158. Isoprocarb 253.Tebupirimfos 64. Cyanophos 159. Isoxathion 254. Teflubenzuron 65.Cycloprothrin 160. Ivermectin 255. Tefluthrin 66. Cyenopyrafen 161.Karanjin 256. Temephos 67. Cyflumetofen 162. Kinoprene 257. Terbufos 68.Cyfluthrin 163. Lamba-Cyhalothrin 258. Tetrachlorvinphos 69. Cyhalothrin164. Lepimectin 259. Tetradifon 70. Cyhexatin 165. Lufenuron 260.Tetramethrin 71. Cymiazole 166. Malathion 261. Thiacloprid 72.Cypermethrin 167. Mecarbam 262. Thiamethoxam 73. Cyphenothrin 168.Mesulfenphos 263. Thiocyclam 74. Cyromazine 169. Metaflumizone 264.Thiodicarb 75. Deltamethrin 170. Metaldehyde 265. Thiofanox 76. DemetonM 171. Methamidophos 266. Thionazin 77. Demeton S 172. Methidathion 267.Thiosultap 78. Demeton-S-methyl 173. Methiocarb 268. Thuringiensin 79.Diafenthiuron 174. Methomyl 269. Tolfenpyrad 80. Diazinon 175.Methoprene 270. Tralomethrin 81. Dichlofenthion 176. Methothrin 271.Transfluthrin 82. Dichlorvos 177. Methoxyfenozide 272. Triarathene 83.Dicofol 178. Metofluthrin 273. Triazamate 84. Dicrotophos 179. Metolcarb274. Triazophos 85. Dicyclanil 180. Metoxadiazone 275. Trichlorfon 86.Diethion 181. Mevinphos 276. Triflumuron 87. Diflovidazin 182.Milbemectin 277. Trimethacarb 88. Diflubenzuron 183. Milbemycin oxime278. Vamidothion 89. Dimefluthrin 184. Monocrotophos 279. Vaniliprole90. Dimethoate 185. Moxidectin 280. XMC (3,5,-Xylylmethylcarbamate) 91.Dimethylvinphos 186. Naled 281. Xylylcarb 92. Dinobuton 187. Nicotine282. Zeta-cypermethrin 93. Dinocap 188. Nitenpyram 283. Zetamethrin 94.Dinotefuran 189. Novaluron 284. ZXI 8901 95. Diofenolan 190.Noviflumuron 285. Demiditraz 286. Afoxolaner 287. Sarolaner 288.Fluralaner

Non-limitative examples of suitable anthelmintics, a few representativeshave anthelmintic activity in addition to the insecticidal andacaricidal activity include:

(A1) Abamectin (A2) Albendazole (A3) Cambendazole (A4) Closantel (A5)Diethylcarbamazine (A6) Doramectin (A7) Emodepside (A8) Eprinomectin(A9) Febantel (A10) Fendendazole (A11) Flubendazole (A12) Ivermectin(A13) Levamisol (A14) Mebendazole (A15) Milbemectin (A16) Milbemycin(A17) Morantel (A18) Moxidectin Oxime (A19) Nitroscanate (A20)Omphalotin (A21) Oxantel (A22) Oxfendazole (A23) Oxibendazole (A24)Phenothiazine (A25) Piperazine (A26) PNU-97333 (A27) PNU-141962 (A28)Praziquantel (A29) Pyrantel (A30) Thiabendazole (A31) Triclabendazoleamino acetonitrile derivatives named in WO2005044784

Non-limitative examples of suitable repellents and detachers include:

(R1 ) DEET (N, N-diethyl-m-toluamide)

(R2) KBR 3023, picaridin, N-butyl-2-oxycarbonyl-(2-hydroxy)-piperidine

(R3) Cymiazole, N,-2,3-dihydro-3-methyl-1,3-thiazol-2-ylidene-2,4-xylidene

The above-specified combination partners are best known to specialistsin this field. Most are described in various editions of the PesticideManual, The British Crop Protection Council, London, in various editionsof the Compendium of Veterinary Products, North American Compendiums,Inc., in various editions of the Compendium of Pesticide Common Namesand in various editions of the Merck Veterinary Manual and The MerckIndex, Merck & Co., Inc., Rahway, N.J., USA.

The pharmaceutical preparation comprising the isothiazoline derivatives,for delivery to a human or other mammal, is preferably in unit dosageform, in which the preparation is subdivided into unit doses containingan appropriate quantity of the active component. The unit dosage formcan be a packaged preparation containing discrete quantities of thepreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet or lozengeitself, or it can be an appropriate number of any of these in packagedform.

The quantity of active component in a unit dose preparation can bevaried or adjusted from about 0.1 mg to about 1000 mg, according to theparticular application and the potency of the active component. Thecomposition can, if desired, also contain other compatible therapeuticagents.

In therapeutic use for the treatment or prevention of a parasiticinfection in a human or other mammal, the compounds utilized in themethod of treatment are administered at an initial dosage of about 0.1mg/kg to about 100 mg/kg per interval. Preferred intervals may be daily,weekly, monthly, quarterly, semi-annually, or annually. The dosages canbe varied depending on the requirements of the patient, for example, thesize of the human or mammal being treated, the severity of the conditionbeing treated, the route of administration, and the potency of thecompound(s) being used. Determination of the proper dosage and route ofadministration for a particular situation is within the skill of thepractitioner. Generally, the treatment will be initiated with smallerdosages which are less than the optimum dose of the compound, which canbe increased in small increments until the optimum effect under theparticular circumstances of the infection is reached. For convenience,the total daily dosage can be divided and administered in portionsduring the day if desired.

The compounds of the present invention, stereoisomers thereof, andcompositions comprising a therapeutically effective amount of a Formula(I) compound, stereoisomer thereof, and veterinarily acceptable saltthereof, and a veterinarily acceptable excipient, diluent, or carrierare useful as ectoparasiticides for the control and treatment ofinfections or infestations manifested by said ectoparasite in an animal.The compounds of the present invention are illustrated herein to haveutility as an ectoparasiticide, in particular, as an acaricide andinsecticide. They may, in particular, be used in the fields ofveterinary medicine, livestock husbandry and the maintenance of publichealth: against acarids, insects, and copepods which are parasitic uponvertebrates, particularly warm-blooded vertebrates, including companionanimals, livestock, and fowl and cold-blooded vertebrates like fish.Non-limiting examples of ectoparasites include: ticks (e.g., Ixodesspp., (e.g., I. ricinus, I. hexagonus), Rhipicephalus spp. (e.g., R.sanguineus), Boophilus spp., Amblyomma spp. (e.g., A. americanum, A.maculatum, A. triste, A. parvum, A. cajennense, A. ovale, A.oblongoguttatum, A. aureolatum, A. cajennense), Hyalomma spp.,Haemaphysalis spp., Dermacentor spp. (e.g., D. variabilis, D. andersoni,D. marginatus), Ornithodorus spp., and the like); mites (e.g.,Dermanyssus spp., Sarcoptes spp. (e.g., S. scabiei), Psoroptes spp.(e.g., P. bovis), Otodectes spp., Chorioptes spp., Demodex spp., (e.g.,D. folliculorum, D. canis, and D. brevis) and the like); chewing andsucking lice (e.g., Damalinia spp., Linognathus spp., Cheyletiella spp.,Haematopinus spp., Solenoptes spp., Trichodectes spp., Felicola spp.,and the like); fleas (e.g., Siphonaptera spp., Ctenocephalides spp., andthe like); biting flies, midges, and mosquitos (e.g., Tabanidae spp.,Haematobia spp., Musca spp., Stomoxys spp., Dematobia spp., Cochliomyiaspp., Simuliidae spp., Ceratopogonidae spp., Psychodidae spp., Aedesspp., Culex spp., Anopheles spp., Lucilia spp., Phlebotomus spp.,Lutzomyia spp., and the like); bed bugs (e.g., insects within the genusCimex and family Cimicidae); and grubs (e.g., Hypoderma bovis, H.lineatum); and copepods (e.g., sea lice within the OrderSiphonostomatoida, including genera Lepeophtheirus and Caligus).

The compound of the present invention can also be used for the treatmentof endoparasites, for example, helminths (e.g., trematodes, cestodes,and nematodes) including heartworm, roundworm, hookworm, whipworm,fluke, and tapeworm. The gastrointestinal roundworms include, forexample, Ostertagia ostertagi (including inhibited larvae), O. lyrata,Haemonchus placei, H. similis, H. contortus, Toxocara canis, T. leonina,T. cati, Trichostrongylus axei, T. colubriformis, T. longispicularis,Cooperia oncophora, C. pectinata, C. punctata, C. surnabada (syn.mcmasteri), C. spatula, Ascaris suum, Hyostrongylus rubidus, Bunostomumphlebotomum, Capillaria bovis, B. trigonocephalum, Strongyloidespapillosus, S. ransomi, Oesophagostomum radiatum, O. dentatum, O.columbianum, O. quadrispinulatum, Trichuris spp., and the like. Otherparasites include: hookworms (e.g., Ancylostoma caninum, A. tubaeforme,A. braziliense, Uncinaria stenocephala); lungworms (e.g., Dictyocaulusviviparus and Metastrongylus spp); eyeworms (e.g., Thelazia spp.);parasitic stage grubs (e.g., Hypoderma bovis, H. lineatum, Dermatobiahominis); kidneyworms (e.g., Stephanurus dentatus); screw worm (e.g.,Cochliomyia hominivorax (larvae); filarial nematodes of the superfamilyFilarioidea and the Onchocercidae Family. Non-limiting examples offilarial nematodes within the Onchocercidae Family include the genusBrugia spp. (i.e., B. malayi, B. pahangi, B. timori, and the like),Wuchereria spp. (i.e., W. bancrofti, and the like), Dirofilaria spp. (D.immitis, D. repens, D. ursi, D. tenuis, D. spectans, D. lutrae, and thelike), Dipetalonema spp. (i.e., D reconditum, D. repens, and the like),Onchocerca spp. (i.e., O. gibsoni, O. gutturosa, O. volvulus, and thelike), Elaeophora spp. (E. bohmi, E. elaphi, E. poeli, E. sagitta, E.schneideri, and the like), Mansonella spp. (i.e., M. ozzardi, M.perstans, and the like), and Loa spp. (i.e., L. loa).

Preferably, the compounds of the present invention are used to treatparasitic infection or infestation, preferably wherein the parasite is aflea or tick. In particularly preferred embodiments, the parasite is C.felis, R. sanguineis, A. americanum, I. scapularis, A. maculate, D.variabilis, or I. ricinus.

In another aspect of the invention, the compound of the presentinvention is useful for treating endoparasiticidal infection fromhelminths/filarial nematodes within the genus Dirofilaria (i.e., D.immitis, D. repens, D. ursi, D. tenuis, and the like).

The compounds of the present invention, stereoisomers thereof, andveterinarily or pharmaceutically acceptable salts thereof, andcompositions comprising compounds of the present invention inconjunction with at least one other veterinary agent are of particularvalue in the control of ectoparasites, endoparasites, and insects whichare injurious to, or spread or act as vectors of diseases in companionanimals, livestock, birds, and fish.

Any of the compounds of the present invention, or a suitable combinationof a compound of the present invention and optionally, with at least oneadditional veterinary agent may be administered directly to the animaland/or indirectly by applying it to the local environment in which theanimal dwells (such as bedding, enclosures, and the like). Directadministration includes contacting the skin, fur, or feathers of asubject animal with the compound(s), or by feeding or injecting thecompounds into the animal.

The Formula (I) compound, stereoisomer thereof, and veterinarilyacceptable salt thereof, and combinations with at least one additionalveterinary agent, as described herein, are believed to be of value forthe treatment and control of the various lifecycle stages of insects andparasites including egg, nymph, larvae, juvenile and adult stages.

The present invention also relates to a method of administering acompound of the present invention alone or in combination with at leastone additional veterinary agent, and optionally a veterinarilyacceptable excipient, diluent, or carrier, to animals in good healthcomprising the application to said animal to reduce or eliminate thepotential for human parasitic infection or infestation from parasitescarried by the animal and to improve the environment in which theanimals inhabit.

The present invention explicitly encompasses those compounds presentedin Table 1. A composition comprising a therapeutically acceptable amountof any of these compounds is also within the scope of the invention. Thecomposition can further comprise a veterinarily acceptable excipient,diluent, carrier, or mixture thereof. Such a composition can beadministered to an animal in need thereof to treat and/or prevent aparasitic infection or infestation. The composition can further comprisean additional veterinary agent, as described herein.

TABLE 1 Ref. No. Compound Name 11-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one26-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-(2,2,2-trifluoroethyl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide 36-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(4-fluorophenyl)sulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine] 4[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-phenyl-methanone 51-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methylsulfonyl-ethanone66-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine] 71-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3-dimethyl-butan-1-one81-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]butan-1-one 91-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-phenyl-ethanone 101-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4,4,4-trifluoro-butan-1-one11[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-(1-naphthyl)methanone 12[(3Z,4Z)-4-allylidene-3-ethylidene-cyclohexa-1,5-dien-1-yl]-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methanone 13[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-(4-morpholinophenyl)methanone 146-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-propylsulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine] 156-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3,3-trifluoropropylsulfonyl)spiro[1H-isobenzofuran-3,3′-azetidine] 166-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-ethyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide 176-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-phenyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide 18[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropyl]methanone 19[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-tetrahydropyran-4-yl-methanone 201′-butyl-6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine] 216-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3-dimethylbutyl)spiro[1H-isobenzofuran-3,3′-azetidine] 221-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methoxy-ethanone 231-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-isopropoxy-ethanone241-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-ethoxy-ethanone 251-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methyl-propan-1-one261-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]propan-1-one 271-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]ethanone 283-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4-ethoxy-cyclobut-3-ene-1,2-dione293-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3-oxo-propanenitrile 301-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2,3,3,3-pentafluoro-propan-1-one311-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2-difluoro-propan-1-one32[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclopropyl]methanone33[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclobutyl]methanone341-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-2,2-dimethyl-propan-1-one 351-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]pentan-1-one 361-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]hexan-1-one 371-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]heptan-1-one 381-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]octan-1-one 391-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]nonan-1-one 406-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-pyrimidin-2-yl-spiro[1H-isobenzofuran-3,3′-azetidine] 416-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-methyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide

Experimental Procedures

Synthesis

The following Examples illustrate the synthesis of representativecompounds of formula (I). These examples are not intended, nor are theyto be construed, as limiting the scope of the embodiments disclosedherein. It will be clear that various embodiments may be practicedotherwise than as particularly described herein. Numerous modificationsand variations are possible in view of the teachings herein and,therefore, are within the scope.

Liquid chromatography—mass spectrometry (LCMS) experiments to determineretention times and associated mass ions were performed using one ormore of the following Methods A, B, and C:

Method A: Waters BEH C18, 3.0×30 mm, 1.7 μm, was used at a temperatureof 50° C. and at a flow rate of 1.5 mL/min, 2 μL injection, mobilephase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase(B) MeOH with 0.1% formic acid; retention time given in minutes.

Method A details: (I) ran on a Binary Pump G1312B with UV/Vis diodearray detector G1315C and Agilent 6130 mass spectrometer in positive andnegative ion electrospray mode with UV PDA detection with a gradient of15-95% (B) in a 2.2 min linear gradient (II) hold for 0.8 min at 95% (B)(III) decrease from 95-15% (B) in a 0.1 min linear gradient (IV) holdfor 0.29 min at 15% (B);

Method B: An Agilent Zorbax Bonus RP, 2.1×50 mm, 3.5 μm, was used at atemperature of 50° C. and at a flow rate of 0.8 mL/min, 2 μL injection,mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile,mobile phase (B) MeOH with 0.1% formic acid; retention time given inminutes.

Method B details: (I) ran on a Binary Pump G1312B with UV/Vis diodearray detector G1315C and Agilent 6130 mass spectrometer in positive andnegative ion electrospray mode with UV-detection at 220 and 254 nm witha gradient of 5-95% (B) in a 2.5 min linear gradient (II) hold for 0.5min at 95% (B) (III) decrease from 95-5% (B) in a 0.1 min lineargradient (IV) hold for 0.29 min at 5% (B).

Method C: An API 150EX mass spectrometer linked to a Shimadzu LC-10AT LCsystem with a diode array detector was used. The spectrometer had anelectrospray source operating in positive and negative ion mode. LC wascarried out using an Agilent ZORBAX XDB 50×2.1 mm C18 column and a 0.5mL/minute flow rate. Solvent A: 95% water, 5% acetonitrile containing0.01% formic acid; Solvent B: acetonitrile. The gradient was shown asbelow. 0-0.5 min: 2% solvent (B); 0.5-2.5 min: 2% solvent B to 95%solvent (B); 2.5-4.0 min: 95% solvent (B); 4.0-4.2 min: 95% solvent (B)to 2% solvent B; 4.2-6.0 min: 2% solvent (B).

EXAMPLES

The following Examples provide a more detailed description of theprocess conditions for preparing compounds of the present invention. Itis to be understood, however, that the invention, as fully describedherein and as recited in the claims, is not intended to be limited bythe details of the following schemes or modes of preparation.

Example 1:1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-oneIntermediate 1: tert-butyl5′-bromo-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate

To a solution of 4-bromo-2-(chloromethyl)-1-iodobenzene (2.0 g, 6.04mmol, 1 eq) in THF (16 mL), isopropylmagnesium chloride lithium chloridecomplex (5.11 mL, 1.3M in THF, 1.1 eq) was added over about 5 min whilethe internal temperature didn't exceed −15° C. Reaction is stirred at−15° C. for 30 min. Then a solution of 1-Boc-3-azetidinone (1.24 g, 1.2eq) in THF (4 mL) was added dropwise; internal temperature at −30° C.The reaction is stirred at room temperature overnight. Reaction wasquenched with a solution of citric acid (14 mL of 1M). This wasextracted with MTBE and organic layer was washed with aqueous NaHCO₃ andbrine, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude yellow oil is submitted to silica gel columnchromatography (0 to 50% ethyl acetate in heptane). 1.6 g of tert-butyl5′-bromo-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate wasobtained.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.47-1.50 (m, 9H) 4.11 (d, J=9.42 Hz, 2H)4.31 (d, J=9.42 Hz, 2H) 5.09 (s, 2H) 7.32-7.38 (m, 2H) 7.49-7.53 (m, 1H)Intermediate 2: tert-butyl5′-acetyl-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate

In a scintillation vial containing 15 mL of ethanol was added Pd(OAc)₂(8.3 mg, 0.037 mmol) and DPPP (31 mg, 0.073 mmol). The reaction vesselwas purged with argon, capped, and heated to 60° C. for 18 hours. Tothis was added tert-butyl5′-bromo-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (250 mg,0.74 mmol) and triethyl amine (0.21 mL, 1.5 mmol) and the mixture washeated to 90° C. for 5 minutes. Butyl vinyl ether (0.2 mL, 1.5 mmol) wasadded and the reaction mixture was heated to 90° C. for 4 hours underargon. The reaction mixture was cooled to room temperature and 1.0 N HCl(21 mL) was added and stirred for 2 h at RT. The reaction wasneutralized with sat-NaHCO₃ and extracted with EtOAc. The organic phasewas concentrated and the residue was purified using 40 g Redi-Sepcolumn, eluting with 0 to 40% ethyl acetate in heptanes, to yield 0.17 gof tert-butyl5′-acetyl-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate. H-NMR(400 MHz, CDCl₃) δ ppm 7.99 (d, 1H, J=8.0 Hz), 7.82 (s, 1H), 7.57 (d,1H, J=8.0 Hz), 5.16 (s, 2H), 4.34 (d, 2H, J=9.5 Hz), 4.15 (d, 2H, J=9.5Hz), 2.63 (s, 3H), 1.49 (s, 9H).

Intermediate 3: 1-(4-chloro-3,5-difluorophenyl)-2,2,2-trifluoroethanone

5-Bromo-2-fluoro-1,3-dichlorobenzene (7.0 g, 28.7 mmol) was stirred atroom temperature in THF (50 mL) under argon and isopropylmagenesiumchloride lithium chloride complex (24.3 mL, 1.3 M in THF, 1.1 eq) wasadded over 1 min and stirred at RT for 30 min. To this was addedpiperidine trifluoroacetamide (5.6 mL, 1.32 eq) over about 1 minute at0° C. and the reaction was stirred at room temperature for 2 h. Thereaction was quenched with aqueous saturated NH₄Cl (50 mL) and extractedwith MTBE (2×50 mL). Solvents were removed under reduced pressure andthe crude product was purified using 12 g Redi-Sep column, eluting with0 to 50% ethyl acetate in heptanes, to yield 3.5 g of1-(4-chloro-3,5-difluorophenyl)-2,2,2-trifluoroethanone. H-NMR (400 MHz,CDCl₃) δ ppm 8.06 (dd, 2H, J₁=6.2 Hz, J₂=0.9 Hz).

Intermediate 4: tert-butyl5′-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate

The starting materials, tert-butyl5′-acetyl-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (5.5 g,18.1 mmol), 1-(4-chloro-3,5-difluorophenyl)-2,2,2-trifluoroethanone(5.44 g, 1.15 eq), were dissolved in a solvent mixture of toluene anda,a,a-trifluorotoluene (40 mL, 1:1, vol/vol) in a 100 mL three neckedround bottom flask equipped with a Dean-Stark head and a condenser ontop on one neck and a nitrogen inlet on another. The reaction mixturewas heated to 110° C. and cesium carbonate (0.5 g) was added. Thereaction mixture was heated for 1 h and then another 0.1 g of cesiumcarbonate was added and heating was continued for another 1 h under avery slow stream of nitrogen. TLC analysis showed still startingmaterial left and another 0.1 g cesium carbonate was added and heatingcontinued for another 1 h. This process was repeated three more times(total amount of cesium carbonate=1.0 g, total reaction time=6 h). Thereaction mixture was cooled to room temperature, filtered through ashort path of silica gel, rinsed with MTBE, and concentrated. The crudeproduct was purified using flash silica gel column chromatography (330 gRediSep column, eluting with 0 to 20% ethyl acetate in heptanes) toyield 8 g of tert-butyl5′-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate.H-NMR (400 MHz, CDCl₃) δ ppm 7.86 (d, 1H, J=8.0 Hz), 7.69 (s, 1H), 7.58(d, 1H, J=8.0 Hz), 7.42 (d, 1H, J=1.4 Hz), 7.25 (d, 2H, J=6.1 Hz), 5.14(s, 2H), 4.34 (d, 2H, J=9.5 Hz), 4.13 (d, 2H, J=9.5 Hz), 1.49 (s, 9H).

Intermediate 5: tert-butyl5′-[3-(3,5-dichloro-4-fluorophenyl)-3-thioacetyl-4,4,4-trifluorobutanoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate

The starting material, tert-butyl5′-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate(3.0 g, 6.0 mmoL), was dissolved in dichloromethane (14 mL) and to thissolution were added thioacetic acid (2.6 mL, 6.0 eq) and 2 drops oftriethylamine and the resulting mixture was stirred at room temperaturefor 96 h under argon. Solvents were removed under reduced pressure andthe crude product was purified via flash silica gel chromatography toyield 1.3 g of tert-butyl5′-[3-(3,5-dichloro-4-fluorophenyl)-3-thioacetyl-4,4,4-trifluorobutanoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate.HNMR (400 MHz, CDCl₃) δ ppm 8.01 (d, 1H, J=8.0 Hz), 7.82 (s, 1H), 7.60(d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=5.8 Hz), 5.23 (d, 1H, J=18.5 Hz), 5.17(s, 2H), 4.35 (d, 2H, J=9.7 Hz), 4.15 (d, 2H, J=9.7 Hz), 3.97 (d, 1H,J=18.5 Hz), 2.33 (s, 3H), 1.50 (s, 9H).

Intermediate 6: tert-butyl5′-[3-(3,5-dichloro-4-fluorophenyl)-3-mercapto-4,4,4-trifluorobutanoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate

To a solution of tert-butyl5′-[3-(3,5-dichloro-4-fluorophenyl)-3-thioacetyl-4,4,4-trifluorobutanoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate(1.3 g, 2.3 mmol) in methanol (23 mL) was added a solution of 25 wt. %sodium methoxide in methanol (0.58 mL, 1.1 eq) and the resulting mixturewas stirred at room temperature for 30 min under nitrogen. The reactionwas quenched with HOAc (0.13 mL), diluted with ethyl acetate, and washedwith brine. The organic extract was concentrated and subjected to silicagel column chromatography (0 to 30% ethyl acetate in heptane) to yield530 mg of the thiol product with trace amount of tert-butyl5′-[3-(3,5-dichloro-4-fluorophenyl)-3-mercapto-4,4,4-trifluorobutanoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate.HNMR (400 MHz, CDCl₃) δ ppm 7.97 (d, 1H, J=8.0 Hz), 7.78 (s, 1H), 7.63(d, 2H, J=5.8 Hz), 7.61 (d, 1H, J=8.0 Hz), 5.17 (s, 2H), 4.35 (d, 2H,J=9.7 Hz), 4.29 (d, 1H, J=18.5 Hz), 4.15 (d, 2H, J=9.7 Hz), 4.00 (d, 1H,J=18.5 Hz), 3.31 (s, 1H), 1.50 (s, 9H).

Intermediate 7: tert-butyl6-[5-(3,5-dichloro-4-fluoro-phenyl)-3-hydroxy-5-(trifluoromethyl)isothiazolidin-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxylate

To a solution of Intermediate 6 (530 mg) in a solution of potassiumhydroxide (182 mg) in water (9 mL) was added a solution ofhydroxylamine-O-sulfonic acid (183 mg, 2 eq) in a solution of potassiumhydroxide (273 mg) in water (18 mL) and the resulting mixture wasstirred at room temperature for 30 min under nitrogen. The mixture wasdiluted with ethyl acetate and washed with brine. The organic extractwas concentrated and subjected to silica gel column chromatography (0 to30% ethyl acetate in heptane) to yield 150 mg of Intermediate 7 as amixture of diastereomers.

Intermediate 8:6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]

To a solution of intermediate 7 in ethylacetate/toluene (1/1), p-toluenesulfonic acid (3 eq) was added. The reaction was stirred and heated at100° C. for 1 h. Solvents are removed under vacuum. The crude wassubjected to reverse phase column chromatography (10 to 100%acetonitrile in aqueous HCl (0.1% vol)) to afford6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine].

Compound 1:1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one

To a solution of intermediate 8 (16 mg, 33.5 nmol, 1 eq) in DMF (1.2mL), N-methylmorpholine (0.2 mmol, 6 eq), 3,3,3-trifluoropropionic acid(0.1 mmol, 3 eq), HOBt (15.4 mg, 3 eq) and EDCl (19.3 mg, 3 eq) wereadded. Reaction was stirred at room temperature overnight. Reaction wasquenched with water (5 drops) and diluted in DMSO. The solution wasdirectly submitted to reverse phase column chromatography (15 to 100%methanol in water). 11 mg of1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-onewere obtained.

¹H NMR (400 MHz, CD₃OD) δ ppm 4.16 (d, J=18.16 Hz, 1H) 4.27-4.37 (m, 2H)4.43 (d, J=18.16 Hz, 1H) 4.52-4.63 (m, 2H) 5.17 (s, 2H) 7.59-7.63 (m,3H) 7.78 (s, 1H) 7.92 (d, J=7.96 Hz, 1H)

Example 26-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-(2,2,2-trifluoroethyl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide

To a solution of intermediate 8 (18 mg, 37.7 nmol, 1 eq) in DCM (1.5mL), TEA (75.4 nmol, 2 eq) and 2,2,2-trifluoroethylisocyanate (5.2 mg,1.1 eq) were added. Reaction was stirred at room temperature overnight.Solvents were evaporated under low pressure to lead to a white solid.Solubilized in EtOAc, it was washed with water and concentrated undervacuum. This was subjected to silica gel column chromatography (10 to100% ethyl acetate in heptane). 15 mg of6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-(2,2,2-trifluoroethyl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamidewere obtained.

¹H NMR (400 MHz, CD₃OD) δ ppm 3.85 (q, J=9.39 Hz, 2H) 4.07-4.13 (m, 1H)4.15 (d, J=18.35 Hz, 1H) 4.19-4.23 (m, 2H) 4.29-4.33 (m, 2H) 4.43 (d,J=18.16 Hz, 1H) 5.15 (s, 2H) 7.56-7.63 (m, 3H) 7.78 (s, 1H) 7.91 (d,J=8.00 Hz, 1H)

Example 36-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(4-fluorophenyl)sulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine]

To a solution of intermediate 8 (14.3 mg, 30 nmol, 1 eq) in1.2-dichloroethane (1.5 mL), TEA (90 nmol, 3 eq) and4-fluorobenzenesulfonyl chloride (6.4 mg, 1.1 eq) were added undernitrogen atmosphere. Reaction was stirred at room temperature for 1 h.Solvents were evaporated under low pressure. Crude was solubilized inEtOAc; organic layer was washed with water and concentrated undervacuum. The oil obtained was subjected to silica gel columnchromatography (8 to 100% ethyl acetate in heptane) to afford6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(4-fluorophenyl)sulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine].

¹H NMR (400 MHz, CD₃OD) δ ppm 3.86 (d, J=17.57 Hz, 1H) 4.06 (q, J=8.98Hz, 4H) 4.21 (d, J=17.57 Hz, 1H) 5.05 (s, 2H) 7.33 (t, J=8.54 Hz, 2H)7.39 (d, J=5.86 Hz, 2H) 7.50 (d, J=8.05 Hz, 1H) 7.64 (s, 1H) 7.72 (d,J=8.05 Hz, 1H) 7.92-7.97 (m, 2H).

Example 46-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-ethyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide

To a solution of intermediate 8 (22 mg, 4.6×10⁻² mmol) and EtN(i-Pr)₂(9.0 mL, 5.1×10⁻² mmol) in THF (0.46 mL) was added ethylisocyanate (4.0mL, 5.1×10⁻² mmol). Reaction stirred at room temperature for 16 h. MeOH(0.5 mL) was added and reaction was allowed to stir for 20 min. beforeit was concentrated in vacuo. The isolated residue was chromatographedover silica gel (0 to 100% EtOAc in heptanes) to give 21 mg of6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-ethyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide(83%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.75 (d, J=8.0 Hz, 1H), 7.66(s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz, 2H), 5.15 (s, 2H),4.34 (d, J=8.8 Hz, 2H), 4.23 (d, J=17.5 Hz, 1H), 4.19-4.10 (m, 3H), 3.88(d, J=17.5 Hz, 1H), 3.36-3.26 (m, 2H), 1.18 (t, J=7.2 Hz, 3H.

Example 56-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-methyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide

To a solution of intermediate 8 (50 mg, 0.10 mmol) and urea 3 (14 mg,0.12 mmol) in DCM (1 mL) was added N-methylmorpholine (14 mL, 0.13mmol). Reaction stirred at room temperature for 24 h before it wasquenched with aq. NaOH (0.25 mL, 1 molar). Mixture stirred for 30 min.before pH was adjusted to approximately 4 with aq. HCl (0.1 molar).Organic layer was separated, washed with sat. aq. NaCl, dried overNa₂SO₄, filtered and concentrated in vacuo. The resultant residue waschromatographed on silica gel (20 to 100% EtOAc in heptanes) to give 39mg of6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-methyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide(70%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.72 (m, 1H), 7.66 (s,1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz, 2H), 5.15 (s, 2H), 4.34(d, J=8.8 Hz, 2H), 4.22 (d, J=17.5 Hz, 1H), 4.16-4.13 (m, 2H), 3.88 (d,J=17.6 Hz, 1H), 2.86 (d, J=4.8 Hz, 3H.

Example 61-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one

To a solution of intermediate 8 (213 mg, 0.446 mmol) in DMF (2.5 mL) wasadded EtN(i-Pr)₂ (0.47 mL, 2.7 mmol), 3,3,3-trifluoropropionic acid(0.12 mL, 1.3 mmol), HOBt hydrate (180 mg, 1.3 mmol), and EDCl.HCl (260mg, 1.3 mmol). Reaction stirred at room temp for 3 h. before it waspoured into water. The suspension was extracted 3× EtOAc and combinedorganic layers were washed 2× saturated aq. NaHCO₃, 2×10% aq. LiCl and1× saturated aq. NaCl. The solution was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was chromatographed on silica gel (0to 50% EtOAc in heptane) to give 199 mg of1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-oneas a white solid (76%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.08 (qd,J=10.28, 2.29 Hz, 2H) 3.88 (d, J=17.42 Hz, 1H) 4.23 (d, J=17.52 Hz, 1H)4.31-4.37 (m, 1H) 4.39-4.48 (m, 2H) 4.60 (d, J=8.93 Hz, 1H) 5.18 (s, 2H)7.39 (d, J=5.86 Hz, 2H) 7.48 (d, J=7.96 Hz, 1H) 7.69 (d, J=4.78 Hz, 1H)7.77 (dd, J=7.66, 4.44 Hz, 1H).

Example 76-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3-dimethyl butyl)spiro[1H-isobenzofuran-3,3′-azetidine]

To a solution of intermediate 8 (26 mg, 0.055 mmol) in DCM (0.33 mL) wasadded a solution of 3,3-dimethylbutryraldehyde (14 mL, 0.11 mmol) andacetic acid (4.8 mL, 0.083 mmol) in DCM (0.33 mL) followed by NaBH₄ (26mg, 0.12 mmol). Reaction stirred at room temperature for 17 h before itwas quenched with sat. aq. NaHCO₃ (1 mL). The mixture was extracted with2× EtOAc. The combined organic layers were washed with water, sat. aq.NaCl, dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas chromatographed over silica gel (15 to 100% EtOAc in heptane) togive 20 mg of6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3-dimethylbutyl)spiro[1H-isobenzofuran-3,3′-azetidine](65%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.69 (m, 2H), 7.62 (s,1H), 7.40 (d, J=5.9 Hz, 2H), 5.10 (s, 2H), 4.23 (d, J=17.5 Hz, 1H), 3.88(d, J=17.5 Hz, 1H), 3.63 (d, J=8.4 Hz, 2H), 3.38-3.34 (m, 2H), 2.59-2.53(m, 2H), 1.35-1.30 (m, 2H), 0.94 (s, 9H).

Example 83-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4-ethoxy-cyclobut-3-ene-1,2-dione

To a solution of intermediate 8 (29 mg, 0.060 mmol) in EtOH (0.3 mL) wasadded 3,4-diethoxy-3-cyclobutene-1,2-dione (8.8 mL, 0.060 mmol). Asuspension formed and additional EtOH (0.3 mL) was added. The reactionstirred at room temperature for 18 h before additional3,4-diethoxy-3-cyclobutene-1,2-dione (2.2 mL, 0.015 mmol) was added.Reaction stirred at room temperature an additional 3 h before it wasconcentrated in vacuo. The residue was chromatographed over silica gel(0 to 100% EtOAc in heptane) to give 27 mg of3-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4-ethoxy-cyclobut-3-ene-1,2-dione(74%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 (d, J=7.9 Hz, 1H), 7.69(s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz, 2H), 5.18 (s, 2H),4.89-4.62 (m, 6H), 4.23 (d, J=17.6 Hz, 1H), 3.89 (d, J=17.6 Hz, 1H),1.46 (t, J=7.1 Hz, 3H).

Example 96-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-pyrimidin-2-yl-spiro[1H-isobenzofuran-3,3′-azetidine]

To a mixture of intermediate 8 (22 mg, 0.045 mmol) and2-(methylsulfonyl)pyrimidine (3.6 mg, 0.054 mmol) was added i-PrOH (1mL). The mixture was irradiated with microwaves (250 watts, 110° C., 200psi) for 90 min. The reaction was allowed to cool to room temperatureand concentrated in vacuo. The residue was chromatographed over silicagel (0 to 100% EtOAc in heptane) to give 15 mg of6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-pyrimidin-2-yl-spiro[1H-isobenzofuran-3,3′-azetidine](59%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=4.8 Hz, 2H), 7.75(d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9Hz, 2H), 6.64 (t, J=4.8 Hz, 1H), 5.21 (s, 2H), 4.53 (d, J=10.0 Hz, 2H),4.39 (d, J=9.6 Hz, 2H), 4.23 (d, J=17.5 Hz, 1H), 3.89 (d, J=17.6 Hz,1H).

By proceeding in a similar fashion to Examples 1-9, the followingcompounds were prepared:

Example 10[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-phenyl-methanone

¹H NMR (400 MHz, CD₃OD) δ ppm 4.15 (d, J=18.21 Hz, 1H) 4.43 (d, J=18.16Hz, 1H) 4.49 (br. s., 2H) 4.59-4.72 (m, 2H) 5.17 (d, J=2.59 Hz, 2H)7.48-7.51 (m, 2H) 7.52-7.55 (m, 1H) 7.60 (d, J=6.05 Hz, 2H) 7.64 (d,J=8.00 Hz, 1H) 7.71-7.75 (m, 2H) 7.78 (s, 1H) 7.91 (d, J=8.10 Hz, 1H)

Example 111-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methylsulfonyl-ethanone

LCMS m/e 596 (M+H); ¹H NMR (400 MHz, CD₃OD) δ ppm 3.15 (s, 3H) 4.08-4.21(m, 3H) 4.25-4.37 (m, 2H) 4.41 (d, J=18.11 Hz, 1H) 4.61-4.72 (m, 2H)5.15 (s, 2H) 7.59 (d, J=6.05 Hz, 2H) 7.63 (d, J=8.05 Hz, 1H) 7.76 (s,1H) 7.88 (d, J=8.10 Hz, 1H).

Example 126-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]

LCMS m/e 477 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87-7.82 (m,1H), 7.75 (d, J=8.7 Hz, 1H), 7.64 (s, 1H), 7.39 (d, J=5.9 Hz, 2H), 5.12(s, 2H), 4.28-4.18 (m, 3H), 3.93-3.78 (m, 3H), 2.84 (br. s., 1H)

Example 131-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3-dimethyl-butan-1-one

LCMS m/e 575 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76 (t, J=6.9Hz, 1H), 7.67 (d, J=6.3 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9Hz, 2H), 5.16 (s, 2H), 4.52 (d, J=9.0 Hz, 1H), 4.41-4.36 (m, 1H), 4.33(d, J=9.1 Hz, 1H), 4.27 (d, J=10.8 Hz, 1H), 4.22 (d, J=17.5 Hz, 1H),3.88 (d, J=17.5 Hz, 1H), 2.09 (s, 2H), 1.10 (s, 9H)

Example 141-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]butan-1-one

LCMS m/e 547 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80-7.73 (m,1H), 7.67 (d, J=5.4 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz,2H), 5.17 (s, 2H), 4.51 (d, J=9.1 Hz, 1H), 4.41-4.36 (m, 1H), 4.32 (d,J=9.1 Hz, 1H), 4.27 (d, J=10.7 Hz, 1H), 4.23 (d, J=17.5 Hz, 1H), 3.88(d, J=17.5 Hz, 1H), 2.17 (t, J=7.4 Hz, 2H), 1.72 (sxt, J=7.4 Hz, 2H),1.00 (t, J=7.4 Hz, 3H)

Example 151-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-phenyl-ethanone

LCMS m/e 595 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.71 (t, J=6.8Hz, 1H), 7.64 (d, J=5.9 Hz, 1H), 7.41-7.28 (m, 8H), 5.18-5.08 (m, 2H),4.47 (d, J=9.3 Hz, 1H), 4.40 (d, J=10.7 Hz, 1H), 4.31-4.16 (m, 3H), 3.86(d, J=17.5 Hz, 1H), 3.65-3.54 (m, 2H)

Example 161-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4,4,4-trifluoro-butan-1-one

LCMS m/e 601 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (dd,J=2.6, 7.8 Hz, 1H), 7.68 (d, J=3.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39(d, J=5.9 Hz, 2H), 5.18 (s, 2H), 4.53 (d, J=8.9 Hz, 1H), 4.44-4.38 (m,1H), 4.35 (d, J=9.1 Hz, 1H), 4.32-4.27 (m, 1H), 4.23 (d, J=17.5 Hz, 1H),3.88 (d, J=17.5 Hz, 1H), 2.62-2.40 (m, 4H)

Example 17[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-(1-naphthyl)methanone

LCMS m/e 631 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.24 (d, J=8.5Hz, 1H), 7.91 (dd, J=8.2, 12.5 Hz, 2H), 7.77 (d, J=8.2 Hz, 1H),7.69-7.60 (m, 3H), 7.60-7.47 (m, 3H), 7.38 (d, J=5.9 Hz, 2H), 5.23-5.05(m, 2H), 4.73-4.56 (m, 2H), 4.35 (d, J=10.1 Hz, 1H), 4.21 (d, J=17.6 Hz,1H), 4.10-4.03 (m, 1H), 3.87 (d, J=17.5 Hz, 1H)

Example 18[(3Z,4Z)-4-allylidene-3-ethylidene-cyclohexa-1,5-dien-1-yl]-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methanone

LCMS m/e 631 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.22 (s, 1H),7.95-7.87 (m, 3H), 7.83-7.70 (m, 2H), 7.68 (s, 1H), 7.63-7.52 (m, 3H),7.39 (d, J=5.9 Hz, 2H), 5.17 (d, J=13.6 Hz, 2H), 4.88-4.60 (m, 2H),4.59-4.51 (m, 2H), 4.22 (d, J=17.5 Hz, 1H), 3.92-3.84 (m, 1H)

Example 19[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-(4-morpholinophenyl)methanone

LCMS m/e 666 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74 (d, J=8.0Hz, 1H), 7.68 (d, J=9.0 Hz, 3H), 7.51 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9Hz, 2H), 6.89 (d, J=8.9 Hz, 2H), 5.17 (s, 2H), 4.81-4.56 (m, 2H),4.53-4.48 (m, 2H), 4.22 (d, J=17.5 Hz, 1H), 3.91-3.84 (m, 5H), 3.29-3.24(m, 4H)

Example 206-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-propylsulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine]

LCMS m/e 583 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (d, J=8.8Hz, 1H), 7.70-7.65 (m, 2H), 7.39 (d, J=5.9 Hz, 2H), 5.15 (s, 2H), 4.36(d, J=9.3 Hz, 2H), 4.26-4.16 (m, 3H), 3.88 (d, J=17.5 Hz, 1H), 3.07-3.01(m, 2H), 1.99-1.87 (m, 2H), 1.11 (t, J=7.5 Hz, 3H)

Example 216-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3,3-trifluoropropylsulfonyl)spiro[1H-isobenzofuran-3,3′-azetidine]

LCMS m/e 635 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.78 (d, J=8.0Hz, 1H), 7.70-7.62 (m, 2H), 7.39 (d, J=5.9 Hz, 2H), 5.18-5.14 (m, 2H),4.41 (d, J=9.4 Hz, 2H), 4.26-4.19 (m, 3H), 3.88 (d, J=17.6 Hz, 1H),3.30-3.24 (m, 2H), 2.77-2.64 (m, 2H)

Example 226-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-ethyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide

LCMS m/e 548 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.75 (d, J=8.0Hz, 1H), 7.66 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz, 2H),5.15 (s, 2H), 4.34 (d, J=8.8 Hz, 2H), 4.23 (d, J=17.5 Hz, 1H), 4.19-4.10(m, 3H), 3.88 (d, J=17.5 Hz, 1H), 3.36-3.26 (m, 2H), 1.18 (t, J=7.2 Hz,3H)

Example 236-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-phenyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide

LCMS m/e 596 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (d, J=8.0Hz, 1H), 7.68 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.6 Hz, 2H),7.39 (d, J=5.9 Hz, 2H), 7.31 (t, J=7.9 Hz, 2H), 7.10-7.04 (m, 1H), 6.14(s, 1H), 5.18 (s, 2H), 4.46 (d, J=8.9 Hz, 2H), 4.30-4.19 (m, 3H), 3.89(d, J=17.6 Hz, 1H)

Example 24[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropyl]methanone

LCMS m/e 669 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (d, J=7.0Hz, 1H), 7.68 (s, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.39 (d, J=5.8 Hz, 2H),6.47 (d, J=9.3 Hz, 1H), 5.17 (s, 2H), 4.61-4.53 (m, 1H), 4.42-4.33 (m,2H), 4.29-4.19 (m, 2H), 3.88 (d, J=17.5 Hz, 1H), 2.06-2.00 (m, 1H),1.65-1.62 (m, 1H), 1.37-1.28 (m, 6H)

Example 25[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-tetrahydropyran-4-yl-methanone

LCMS m/e 589 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76 (t, J=6.5Hz, 1H), 7.67 (d, J=5.3 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9Hz, 2H), 5.17 (s, 2H), 4.55 (d, J=9.0 Hz, 1H), 4.42-4.35 (m, 2H),4.31-4.26 (m, 1H), 4.22 (d, J=17.5 Hz, 1H), 4.05 (d, J=11.6 Hz, 2H),3.88 (d, J=17.5 Hz, 1H), 3.44 (dt, J=2.1, 11.7 Hz, 2H), 2.54-2.44 (m,1H), 1.99-1.86 (m, 2H), 1.67 (d, J=11.8 Hz, 2H)

Example 261′-butyl-6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]

LCMS m/e 533 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81-7.70 (m,2H), 7.62 (s, 1H), 7.40 (d, J=5.9 Hz, 2H), 5.10 (s, 2H), 4.23 (d, J=17.5Hz, 1H), 3.91-3.84 (m, 1H), 3.63 (d, J=6.3 Hz, 2H), 3.38 (d, J=8.3 Hz,2H), 2.59-2.52 (m, 2H), 1.45-1.35 (m, 5H)

Example 276-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3-dimethylbutyl)spiro[1H-isobenzofuran-3,3′-azetidine]

LCMS m/e 561 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.69 (m,2H), 7.62 (s, 1H), 7.40 (d, J=5.9 Hz, 2H), 5.10 (s, 2H), 4.23 (d, J=17.5Hz, 1H), 3.88 (d, J=17.5 Hz, 1H), 3.63 (d, J=8.4 Hz, 2H), 3.38-3.34 (m,2H), 2.59-2.53 (m, 2H), 1.35-1.30 (m, 2H), 0.94 (s, 9H)

Example 281-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methoxy-ethanone

LCMS m/e 549 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76 (d, J=7.6Hz, 1H), 7.67 (br. s., 1H), 7.50 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz,2H), 5.16 (br. s., 2H), 4.63 (d, J=10.4 Hz, 1H), 4.53-4.42 (m, 2H), 4.34(d, J=10.9 Hz, 1H), 4.22 (d, J=17.5 Hz, 1H), 4.08 (s, 2H), 3.88 (d,J=17.4 Hz, 1H), 3.43 (s, 3H)

Example 291-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-isopropoxy-ethanone

LCMS m/e 577 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76 (dd,J=3.3, 7.7 Hz, 1H), 7.67 (d, J=4.2 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.39(d, J=5.9 Hz, 2H), 5.16 (s, 2H), 4.68 (d, J=10.5 Hz, 1H), 4.55 (d,J=10.5 Hz, 1H), 4.46-4.40 (m, 1H), 4.35-4.29 (m, 1H), 4.23 (d, J=17.5Hz, 1H), 4.12 (s, 2H), 3.88 (d, J=17.6 Hz, 1H), 3.66 (td, J=6.1, 12.2Hz, 1H), 1.20 (d, J=6.1 Hz, 6H)

Example 301-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-ethoxy-ethanone

LCMS m/e 563 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.74 (m,1H), 7.69-7.66 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz, 2H),5.17 (s, 2H), 4.68-4.64 (m, 1H), 4.55-4.51 (m, 1H), 4.46-4.41 (m, 1H),4.35-4.30 (m, 1H), 4.23 (d, J=17.5 Hz, 1H), 4.13-4.12 (m, 2H), 3.90 (s,1H), 3.57 (q, J=7.0 Hz, 2H), 1.24 (s, 3H)

Example 311-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methyl-propan-1-one

LCMS m/e 547 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.73 (m,1H), 7.67 (d, J=4.8 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz,2H), 5.17 (s, 2H), 4.54 (d, J=9.1 Hz, 1H), 4.41-4.32 (m, 2H), 4.30-4.19(m, 2H), 3.88 (d, J=17.6 Hz, 1H), 2.57-2.49 (m, 1H), 1.17 (t, J=6.2 Hz,6H)

Example 321-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]propan-1-one

LCMS m/e 533 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80-7.73 (m,1H), 7.67 (d, J=4.8 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz,2H), 5.16 (s, 2H), 4.49 (s, 1H), 4.37 (s, 1H), 4.34-4.25 (m, 2H), 4.22(d, J=17.5 Hz, 1H), 3.88 (d, J=17.4 Hz, 1H), 2.26-2.18 (m, 2H), 1.19 (t,J=7.5 Hz, 3H)

Example 331-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]ethanone

LCMS m/e 519 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76 (d, J=5.5Hz, 1H), 7.67 (d, J=4.7 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9Hz, 2H), 5.17 (s, 2H), 4.52 (d, J=9.1 Hz, 1H), 4.42-4.31 (m, 2H),4.30-4.19 (m, 2H), 3.88 (d, J=17.5 Hz, 1H), 1.98 (s, 3H)

Example 341-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-1,1-dioxo-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one

LCMS m/e 619 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.11 (d, J=7.9Hz, 1H), 8.01 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.56 (d, J=5.8 Hz, 2H),5.26 (s, 2H), 4.66 (d, J=9.6 Hz, 1H), 4.54-4.44 (m, 2H), 4.38 (d, J=11.0Hz, 1H), 4.26 (d, J=17.8 Hz, 1H), 4.03 (d, J=17.8 Hz, 1H), 3.17-3.03 (m,2H)

Example 353-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3-oxo-propanenitrile

LCMS m/e 544 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80-7.76 (m,1H), 7.71-7.68 (m, 1H), 7.54-7.50 (m, 1H), 7.39 (d, J=5.9 Hz, 2H), 5.18(s, 2H), 4.69-4.64 (m, 1H), 4.56-4.45 (m, 2H), 4.39-4.34 (m, 1H),4.26-4.20 (m, 1H), 3.91-3.85 (m, 1H), 3.37 (s, 2H)

Example 361-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2,3,3,3-pentafluoro-propan-1-one

LCMS m/e 575 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.83 (d, J=8.0Hz, 1H), 7.76-7.72 (m, 2H), 7.39 (d, J=5.9 Hz, 2H), 5.15 (s, 2H), 4.76(d, J=9.4 Hz, 2H), 4.62 (d, J=10.2 Hz, 2H), 4.23 (d, J=17.6 Hz, 1H),3.88 (d, J=17.7 Hz, 1H)

Example 371-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2-difluoro-propan-1-one

LCMS m/e 567 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (d, J=7.9Hz, 1H), 7.69-7.65 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.8 Hz,2H), 5.20-5.14 (m, 2H), 4.77 (d, J=11.6 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H),4.51-4.46 (m, 1H), 4.39-4.34 (m, 1H), 4.23 (d, J=17.5 Hz, 1H), 3.88 (d,J=17.5 Hz, 1H), 2.81 (s, 3H)

Example 38[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclopropyl]methanone

LCMS m/e 613 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (d, J=8.0Hz, 1H), 7.70-7.67 (m, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz,2H), 5.17 (s, 2H), 4.75-4.27 (m, 4H), 4.23 (d, J=17.5 Hz, 1H), 3.88 (d,J=17.5 Hz, 1H), 0.91-0.83 (m, 4H)

Example 39[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclobutyl]methanone

LCMS m/e 627 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.75 (d, J=7.6Hz, 1H), 7.67 (br. s., 1H), 7.45 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz,2H), 5.16 (d, J=3.9 Hz, 2H), 4.58 (d, J=9.3 Hz, 1H), 4.50-4.44 (m, 1H),4.42-4.33 (m, 2H), 4.22 (d, J=17.5 Hz, 1H), 3.87 (d, J=17.3 Hz, 1H),2.78-2.58 (m, 2H), 2.56-2.38 (m, 2H), 2.22-2.07 (m, 1H), 1.97-1.85 (m,1H)

Example 401-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-2,2-dimethyl-propan-1-one

LCMS m/e 615 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76 (d, J=7.8Hz, 1H), 7.67 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz, 2H),5.31 (s, 2H), 5.16 (s, 2H), 4.22 (d, J=17.5 Hz, 1H), 3.88 (d, J=17.5 Hz,1H), 3.50 (s, 2H), 1.48 (s, 6H)

Example 411-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]pentan-1-one

LCMS m/e 561 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.72 (m,1H), 7.70-7.65 (m, 1H), 7.49 (s, 1H), 7.39 (d, J=5.9 Hz, 2H), 5.16 (s,2H), 4.53-4.48 (m, 1H), 4.41-4.36 (m, 1H), 4.33-4.30 (m, 1H), 4.29-4.25(m, 1H), 4.22 (d, J=17.5 Hz, 1H), 3.91-3.85 (m, 1H), 2.22-2.16 (m, 2H),1.72-1.60 (m, 2H), 1.39 (d, J=7.4 Hz, 2H), 0.97-0.92 (m, 3H)

Example 421-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]hexan-1-one

LCMS m/e 575 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.73 (m,1H), 7.67 (d, J=5.6 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz,2H), 5.16 (s, 2H), 4.49 (s, 1H), 4.37 (s, 1H), 4.31 (d, J=17.4 Hz, 2H),4.22 (d, J=17.5 Hz, 1H), 3.88 (d, J=17.5 Hz, 1H), 2.37-2.32 (m, 1H),2.18 (t, J=7.6 Hz, 2H), 1.37-1.33 (m, 4H), 0.94-0.88 (m, 4H)

Example 431-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]heptan-1-one

LCMS m/e 589 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.73 (m,1H), 7.69-7.65 (m, 1H), 7.50-7.46 (m, 1H), 7.39 (d, J=5.9 Hz, 2H), 5.17(s, 2H), 4.53-4.48 (m, 1H), 4.41-4.35 (m, 1H), 4.34-4.25 (m, 2H),4.25-4.19 (m, 1H), 3.92-3.83 (m, 1H), 2.19 (s, 2H), 1.72-1.65 (m, 2H),1.35-1.31 (m, 6H), 0.84 (d, J=2.2 Hz, 3H)

Example 441-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]octan-1-one

LCMS m/e 603 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.73 (m,1H), 7.69-7.65 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz, 2H),5.16 (s, 2H), 4.53-4.48 (m, 1H), 4.37 (s, 1H), 4.28 (s, 2H), 4.22 (d,J=17.5 Hz, 1H), 3.90 (s, 1H), 2.18 (t, J=7.6 Hz, 2H), 1.68 (br. s., 2H),1.35-1.29 (m, 9H), 0.91-0.88 (m, 9H)

Example 451-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]nonan-1-one

LCMS m/e 617 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.73 (m,1H), 7.67 (d, J=5.7 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz,2H), 5.17 (s, 2H), 4.51 (d, J=9.1 Hz, 1H), 4.41-4.36 (m, 1H), 4.29 (dd,J=10.0, 17.8 Hz, 2H), 4.22 (d, J=17.5 Hz, 1H), 3.88 (d, J=17.5 Hz, 1H),2.18 (t, J=7.6 Hz, 2H), 1.70-1.65 (m, 2H), 1.32 (d, J=7.5 Hz, 9H),0.90-0.86 (m, 13H)

Example 466-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-pyrimidin-2-yl-spiro[1H-isobenzofuran-3,3′-azetidine]

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=4.8 Hz, 2H), 7.75 (d,J=8.0 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz,2H), 6.64 (t, J=4.8 Hz, 1H), 5.21 (s, 2H), 4.53 (d, J=10.0 Hz, 2H), 4.39(d, J=9.6 Hz, 2H), 4.23 (d, J=17.5 Hz, 1H), 3.89 (d, J=17.6 Hz, 1H)

Example 476-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-methyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide

LCMS m/e 534 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79-7.72 (m,1H), 7.66 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.9 Hz, 2H), 5.15(s, 2H), 4.34 (d, J=8.8 Hz, 2H), 4.22 (d, J=17.5 Hz, 1H), 4.16-4.13 (m,2H), 3.88 (d, J=17.6 Hz, 1H), 2.86 (d, J=4.8 Hz, 3H)

Evaluation

The biological activity of compounds of the present invention was testedusing the test methods described below.

R. sanguineus, D. variablis, A. americanum, and I. scapularis ResidualAdult Contact Assay

A solution of the test compounds was used to coat the inner wall ofglass vials and to treat two filter papers. Once dried, one filter paperwas placed in the cap of the vial and the other in the bottom of thevial. Each treated vial was infested with 10 ticks. Contact of the tickswith residues was induced by holding the vials in a controlledenvironment and assessment was performed at 12, 24 and 48 hours afterapplication in comparison with untreated glass vials and solvent-treatedglass vials. Compounds were tested in duplicate and two separate trials(n=4).

Preferred compounds of the invention are generally active at below 500ppm at 48 hours in the assay.

Compound reference numbers 1, 2, 4-10, 14-16, 19, 22-27, 29, 31, 32,34-38, and 41 were active at below 50 ppm at 48 hours in this assay and,as such, are especially preferred for such intended use.

Ctenocephalides felis Residual Contact Assay

A solution of the test compounds, individually and in combination wasdispensed onto a substrate placed into a glass vial. The treated surfacewas allowed to dry before infesting each vial with 10 adultCtenocephalides felis. The treated vials were held in a controlledenvironment and assessment was performed at 6, 24 and 48 hours afterapplication in comparison with untreated controls glass vials andsolvent-treated glass vials. Compounds were tested in duplicate and twoseparate trials (n=4).

Preferred compounds of the invention are generally active at below 500ppm at 48 hours in the assay.

Compound reference numbers 1, 2, 4, and 5 were active at below 50 ppm at48 hours in this assay and, as such, are especially preferred for suchintended use.

In Vitro Evaluation of Ingestion Activity Against Fleas (Ctenocephalidesfelis)

For flea ingestion tests, an aliquot of each compound stock was added toorganic bovine blood contained in an artificial feeding container, witha final DMSO concentration of 0.5%. Ten newly emerged unfed fleas,Ctenocephalides felis, from a laboratory colony, 0-7 days old, wereaspirated into a chamber and exposed to the appropriate feedingcontainer and held in a controlled environment at 35° C. Fleas wereevaluated for % mortality at 24, 48, and 72 hours post infestation.Fleas showing normal movement and/or jumping ability were consideredviable and those showing no movement after tapping the vials were scoredas dead. The compound+blood mixture was replaced every 24 hours.

Preferred compounds of the invention are generally active at below 500ppm at 24 hours in this assay.

Compound reference numbers 1, 2, 4-10, 14-17, 19, 20, 22-27, 29-38, and41 were active at below 50 ppm at 48 hours in this assay and, as such,are especially preferred for such intended use.

Dirofilaria immitis Microfilariae Motility Assay

Dirofilaria immitis microfilariae are isolated by filtration from bloodof an infected beagle dog allowed to incubate at 37 C/5% CO₂/95% RH inRPMI media. For assay 500 microfilariae are added into 96-well platesfollowed by addition of compounds diluted in DMSO for single-point ordose response (5-point) analysis. Ivermectin or emodepside are includedas a positive control and DMSO-only wells are included as negativecontrols. Plates containing parasites and compounds are incubated at 37°C./5% CO₂/95% RH for 72 hours and motility is assessed using an LCDcamera imaging system. Percent motility inhibition values are generatedrelative to the average of the DMSO-only wells. For dose responseanalysis, data points were averaged and curve fitting software is usedto generate sigmoidal curves for the determination of EO₅₀ values (i.e.the effective concentration to kill 50% of the organism).

Preferred compounds of the invention are generally active at below 100μM in this assay.

Particularly preferred compounds are active below 10 μM, such ascompounds 1, 13, 16-17, 19-27, 29-31, 35, 36, 40, and 41, and thereforeare preferred for such use.

In Vitro Evaluation of Ingestion Activity Against Mosquitoes (Aedesaegypti)

A solution of test compounds is added to bovine blood contained in afeeding chamber to reach the desired final concentration. Blood spikedwith DMSO is prepared to serve as control. Adult female mosquitoes areintroduced at the bottom of the chamber and allowed to feed on bloodmixtures containing DMSO or test compounds for 30 minutes. Fullyengorged mosquitoes are sorted into clean chambers after the blood mealand monitored for survival over 3 days. Replicates containing 10mosquitoes are performed with each test compound concentration andresults calculated as % mortality at specific time points.

Preferred compounds of the invention are generally active at below 500ppm at 20 hours in this assay.

Compound reference numbers 1, 6-8, 10, 12, 16, 17, 19, 20, 22-27, 29,30, 35, and 41 were active at below 1 ppm at 20 hours in this assay andare especially preferred for such intended use.

In Vitro Evaluation of Contact Activity Against Mosquitoes (Aedesaegypti)

A solution of the test compound is used to coat the inner walls of glassvials and allowed to dry overnight. Five female Aedes aegypti adults areadded to each vial. Contact of the mosquitoes is induced by holding thevials in a controlled environment and assessment of mortality/knockdownis performed at 24 hours after application in comparison tosolvent-treated glass vials. Compounds are tested in duplicate on atotal of 10 mosquitoes/treatment dose.

Preferred compounds of the invention are generally active at below 500ppm at 48 hours in the assay.

In Vitro Evaluation of Contact Activity Against Flies (Stomoxyscalcitrans)

A solution of the test compounds is added to a piece of filter paperembedded in a petri dish and allowed to dry overnight. Ten 2-3 day oldadult flies are added to each petri dish and a sucrose-soaked dentalwick is added as a food source. Flies are held at room temperature andassessed for mortality/knockdown at desired time points.

Preferred compounds of the invention are generally active at below 500ppm at 48 hours in the assay.

In Vitro Flea Activity—Comparison with Fluralaner, Afoxolaner, and(+/−)Sarolaner

Using known and described methods, Compound Reference Number 1 wascompared to fluralaner, afoxolaner, and (+/−)sarolaner in contact andingestion assays. Fluralaner is sold under the tradename Bravecto® byMerck Animal Health. Afoxolaner is sold under the tradename Nexgard® byMerial Ltd. Sarolaner is sold under the tradename Simparica® by Zoetis,Inc. As noted herein, for the comparison studies racemic sarolaner“(+/−)” was used.

The results are provided:

Ingestion EC50 Contact EC50 Compound 2 h, ppm 24 h, ppm 48 h, ppmCompound Ref. No. 1 2.6 ± 0.3 0.20 ± 0.10 29.0 ± 0.3 Fluralaner 1.6 ±0.7 0.06 ± 0.02 >50 Afoxolaner 6.0 ± 2.9 0.13 ± 0.05 >50 (+/−)SarolanerNT 1.23 ± 0.11 NT

The compounds of the present invention, as represented by compoundreference number 1, provide comparable potency by ingestion and superiorpotency by contact to commercially available standards of treatment.

In Vitro Tick Activity—Comparison with Fluralaner, Afoxolaner, and(+/−)Sarolaner

Using known and described methods, Compound Reference Number 1 wascompared to fluralaner, afoxolaner, and (+/−)sarolaner in contact assayson several tick species. The results are provided:

R. sanguineus D. variabilis A. americanum I. scapularis Contact EC₅₀Contact EC₅₀ Contact EC₅₀ Contact EC₅₀ Compound 24 h, ppm 24 h, ppm 24h, ppm 24 h, ppm Comp. Ref. No. 1 17.0 ± 3.8  12.2 ± 0.6 13.5 ± 5.1 2.0± 0.4 fluralaner 37.1 ± 16.3 18.4 ± 3.0 12.4, >50 6.4 ± 3.3afoxolaner >50 >50 31.6, >50 17.8 ± 5.9  (+/−)sarolaner 37.8 ± 12.2 R.sanguineus D. variabilis A. americanum I. scapularis Contact EC₅₀Contact EC₅₀ Contact EC₅₀ Contact EC₅₀ Compound 48 h, ppm 48 h, ppm 48h, ppm 48 h, ppm Comp. Ref. No. 1  4.6 ± 3.0 5.0 ± 1.6 2.7 ± 0.4 0.06 ±0.02 fluralaner  9.8 ± 5.0 4.9 ± 1.4 20.4 ± 10.7 1.3 ± 0.2 afoxolaner20.2 ± 5.0 12.35 ± 0.5  11.3 ± 2.3  5.31 ± 1.8  (+/−)sarolaner 12.7 ±0.1

The compounds of the present invention, as represented by compoundreference number 1, provide superior potency by contact to commerciallyavailable standards of treatment.

All publications, patents and patent applications cited in thisspecification are incorporated herein by reference for the teaching towhich such citation is used.

Test compounds for the experiments described herein were employed infree or salt form.

The specific responses observed may vary according to and depending onthe particular active compound selected or whether there are presentcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with practice of the present invention.

Although specific embodiments of the present invention are hereinillustrated and described in detail, the invention is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present invention and should not be construed as constituting anylimitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included with the scope ofthe appended claims.

1.-20. (canceled)
 21. A method for treating a mammal for one or more of(i) an ectoparasite infection or infestation, or (ii) an endoparasiteinfection or infestation, comprising administering to a mammal acompound of Formula (I), or a pesticidal, veterinary, orpharmaceutically acceptable salt thereof:

wherein each R^(1A), R^(1B), and R^(1C) individually is hydrogen, alkyl,halogen, or haloalkyl; R² is haloalkyl; X is bond, C(O), SO₂, or C(O)NH;R³ is hydrogen, optionally substituted alkyl, optionally substitutedhaloalkyl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl.
 22. The method of claim 21, wherein the ectoparasite isselected from ticks, mites, chewing lice, sucking lice, fleas, bitingflies, midges, mosquitos, bed bugs, grubs, and copepods.
 23. The methodof claim 22, wherein the ectoparasite is selected from Ixodes spp., I.ricinus, I. hexagonus, Rhipicephalus spp., R. sanguineus, Boophilusspp., Amblyomma spp., A. americanum, A. maculatum, A. triste, A. parvum,A. cajennense, A. ovale, A. oblongoguttatum, A. aureolatum, A.cajennense, Hyalomma spp., Haemaphysalis spp., Dermacentor spp., D.variabilis, D. andersoni, D. marginatus, Ornithodorus spp., Dermanyssusspp., Sarcoptes spp., S. scabiei, Psoroptes spp., P. bovis, Otodectesspp., Chorioptes spp., Demodex spp., D. folliculorum, D. canis, D.brevis, Damalinia spp., Linognathus spp., Cheyletiella spp.,Haematopinus spp., Solenoptes spp., Trichodectes spp., Felicola spp.,Siphonaptera spp., Ctenocephalides spp., Tabanidae spp., Haematobiaspp., Musca spp., Stomoxys spp., Dematobia spp., Cochliomyia spp.,Simuliidae spp., Ceratopogonidae spp., Psychodidae spp., Aedes spp.,Culex spp., Anopheles spp., Lucilia spp., Phlebotomus spp., Lutzomyiaspp., insects within the genus Cimex and family Cimicidae, Hypodermabovis, H. lineatum, or insects within the Order Siphonostomatoida,including genera Lepeophtheirus and Caligus.
 24. The method of claim 21,wherein the endoparasite is selected from helminths, gastrointestinalroundworms, hookworms, lungworms, eyeworms, parasitic stage grubs,kidneyworms, screw worm, and filarial nematodes of the superfamilyFilarioidea and the Onchocercidae Family.
 25. The method of claim 24,wherein the endoparasite is selected from trematodes, cestodes,nematodes, heartworm, roundworm, hookworm, whipworm, fluke, tapeworm,Ostertagia ostertagi, O. lyrata, Haemonchus placei, H. similis, H.contortus, Toxocara canis, T. leonina, T. cati, Trichostrongylus axei,T. colubriformis, T. longispicularis, Cooperia oncophora, C. pectinata,C. punctata, C. surnabada (syn. mcmasteri), C. spatula, Ascaris suum,Hyostrongylus rubidus, Bunostomum phlebotomum, Capillaria bovis, B.trigonocephalum, Strongyloides papillosus, S. ransomi, Oesophagostomumradiatum, O. dentatum, O. columbianum, O. quadrispinulatum, Trichurisspp., Ancylostoma caninum, A. tubaeforme, A. braziliense, Uncinariastenocephala); Dictyocaulus viviparous, Metastrongylus spp, Thelaziaspp., Hypoderma bovis, H. lineatum, Dermatobia hominis,Stephanurusdentatus, Cochliomyia hominivorax, B. malayi, B. pahangi, B.timori, Wuchereria spp., W. bancrofti, Dirofilaria spp., D. immitis, D.repens, D. ursi, D. tenuis, D. spectans, D. lutrae, Dipetalonema spp., Dreconditum, D. repens, Onchocerca spp., O. gibsoni, O. gutturosa, O.volvulus, Elaeophora spp., E. bohmi, E. elaphi, E. poeli, E. sagitta, E.schneider, Mansonella spp., M. ozzardi, M. perstans, Loa spp., and L.loa.
 26. The method of claim 21, wherein: each R^(1A), R^(1B), andR^(1C) individually is halogen, haloalkyl, or alkyl; R² is haloalkyl; Xis a bond, C(O), SO₂, or C(O)NH; and R³ is alkyl, haloalkyl, or aryl.27. The method of claim 21, wherein: each R^(1A), R^(1B), and R^(1C)individually is halogen; R² is perfluoroalkyl; X is —C(O)—, —SO₂—, or—C(O)NH—; and R³ is haloalkyl.
 28. The method of claim 21, wherein: eachR^(1A) and R^(1C) is a halogen and R^(1B) is a different halogen; R² ishaloalkyl, preferably —CF₃; X is —C(O)—; and R³ is haloalkyl, preferably—CH₂CF₃.
 29. The method of claim 21, wherein: each R^(1A) and R^(1C) is—Cl and R^(1B) is —F; R² is —CF₃; X is —C(O)—; and R³ is haloalkyl,preferably —CH₂CF₃.
 30. The method of claim 21, wherein: each R^(1A) andR^(1C) is —Cl and R^(1B) is —F; R² is —CF₃; X is a bond, C(O), SO₂, orC(O)NH; and R³ is hydrogen, optionally substituted alkyl, optionallysubstituted haloalkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl.
 31. The method of claim 21, wherein R³ is alkyl;alkyl substituted with one or more alkoxy, alkylsulfonyl, cyano, oraryl; haloalkyl; cycloalkyl; cycloalkyl substituted with one or morealkyl, alkenyl, haloalkyl, haloalkenyl, alkoxy, or carbonyl;heterocyclyl; aryl; aryl substituted with one or more halogen; orheteroaryl.
 32. The method of claim 21, wherein the compound is selectedfrom:6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-(2,2,2-trifluoroethyl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(4-fluorophenyl)sulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine];[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-phenyl-methanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methylsulfonyl-ethanone;6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine];1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3-dimethyl-butan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]butan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-phenyl-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4,4,4-trifluoro-butan-1-one;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-(1-naphthyl)methanone;[(3Z,4Z)-4-allylidene-3-ethylidene-cyclohexa-1,5-dien-1-yl]-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methanone;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-(4-morpholinophenyl)methanone;6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-propylsulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine];6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3,3-trifluoropropylsulfonyl)spiro[1H-isobenzofuran-3,3′-azetidine];6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-ethyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-phenyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropyl]methanone;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-tetrahydropyran-4-yl-methanone;1′-butyl-6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine];6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3-dimethyl butyl)spiro[1H-isobenzofuran-3,3′-azetidine];1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methoxy-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-isopropoxy-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-ethoxy-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methyl-propan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]propan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]ethanone;3-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4-ethoxy-cyclobut-3-ene-1,2-dione;3-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3-oxo-propanenitrile;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2,3,3,3-pentafluoro-propan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2-difluoro-propan-1-one;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclopropyl]methanone;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclobutyl]methanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-2,2-dimethyl-propan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]pentan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]hexan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]heptan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]octan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]nonan-1-one;6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-pyrimidin-2-yl-spiro[1H-isobenzofuran-3,3′-azetidine];and6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-methyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide,or a pesticidal, veterinary, or pharmaceutically acceptable saltthereof.
 33. The method of claim 21, wherein the compound is selectedfrom:6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-(2,2,2-trifluoroethyl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-phenyl-methanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methylsulfonyl-ethanone;6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine];1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3-dimethyl-butan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]butan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-phenyl-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4,4,4-trifluoro-butan-1-one;6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-propylsulfonyl-spiro[1H-isobenzofuran-3,3′-azetidine];6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-1′-(3,3,3-trifluoropropylsulfonyl)spiro[1H-isobenzofuran-3,3′-azetidine];6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-ethyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-phenyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-tetrahydropyran-4-yl-methanone;1′-butyl-6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine];1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methoxy-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-isopropoxy-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-ethoxy-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methyl-propan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]propan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]ethanone;3-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3-oxo-propanenitrile;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2,3,3,3-pentafluoro-propan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2,2-difluoro-propan-1-one;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclopropyl]methanone;[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-[1-(trifluoromethyl)cyclobutyl]methanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-2,2-dimethyl-propan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]pentan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]hexan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]heptan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]octan-1-one;and6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-methyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide,or a pesticidal, veterinary, or pharmaceutically acceptable saltthereof.
 34. The method of claim 21, wherein the compound is selectedfrom:6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-(2,2,2-trifluoroethyl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methylsulfonyl-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]butan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-4,4,4-trifluoro-butan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-2-methoxy-ethanone;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]propan-1-one;1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]ethanone;and6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-methyl-spiro[1H-isobenzofuran-3,3′-azetidine]-1′-carboxamide,or a pesticidal, veterinary, or pharmaceutically acceptable saltthereof.